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150 Cards in this Set
- Front
- Back
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Catabolic vs Anabolic pathway characteristics
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Catabolic:
- convergent process - end products are simple molecules - release energy - breaks down things Anabolic - divergent process - end products are complex molecules - requires energy - builds something |
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Key types of reactions in metabolism
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- oxidation/reduction: electron transfer
- ligation requiring ATP cleavage: formation of covalent bonds (C-C bonds) - Isomerization: rearrangement of atoms to form isomers - Group transfer: transfer of a functional group between molecules - Hydrolytic: cleave of bonds by addition of water - Addition/removal of functional groups:..to form or saturate double bonds |
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Metabolic carriers formed from vitamins:
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NADH/NADPH: nicotinate (niacin)
FADH2/FMNH2: riboflavin (Vit. B2) Coenzyme A: Pantothenate Thiamine pyrophosphate (TPP): thiamine (Vit B2) Biotin: biotin Tetrahydrofolate: folate |
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Mechanisms fro regulating enzymes
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- isoforms: enzymes specific to different organs that have different physical characteristics but essentially do the same thing.
- Substrate concentrations: most pathways operate at equilibrium/around enzyme Km so small [ ] does a lot -product inhibition: allosteric - allosteric regulation: change binding site conformation - covalent modification: often phosphorylation by ATP or suicide modification - Changes in enzyme protein concentration: induction (increase expression), repression (decrease expression), sequestration, degradation |
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PKA activation
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- PKA is inactivated by regulatory subunits.
-cAMP (triggered by glucagon/insulin) binds to the regulatory subunits releasing the active PKA. -PKA then activates/deactivates other molecules by phosphorylation |
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Time scale for enzyme regulation
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Min: substrate availability, allosteric regulation
Min-hrs: covalent modication Hrs-days: amount of enzyme (degradation/transcriptional regulation) |
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Energy Charge
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- amount of energy readily available in the cell to do work. Range from 0-1 (all AMP-all ATP).
- Catabolic pathways are inhibited by high EC while anabolic are activated (vice versa) - Energy charge is buffered and ranges from 0.8-0.95 EC= [ATP] + ½[ADP] / [ATP]+[ADP]+[AMP] |
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Common themes underlying metabolic pathways
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- Irreversibility: so forward/back can't occur simultaneously and can be regulated separately. Only a couple steps are irreversible, most are at equilibrium
- committed step: usually the first irreversible step, commits the product to the pathway - regulated: prevents synthesis of unneeded metabolites, often occurs at branch points - Compartmentalization: segregated opposing reactions within the cell and within the body |
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Enzymes
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- Designed to catalyze specific chemical transformations of biological molecules
- accelerates the rate of a reaction (~10^9 fold) by lowering the activation energy, but is not altered itself in the process & doesn't change the ΔG or Keq. - Most are proteins - enable reactions under mild conditions - increase reaction specificity (only certain binding site conformations: lock & key vs induced fit) - enable regulation (of the reaction and the overall pathway) |
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Coenzymes
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= small molecules or metals that bind to a protein
(apoenzyme) to constitute a functional enzyme (holoenzyme). - Neither the apoenzyme or the coenzyme by themselves can function as an enzyme. - Ex: Vitamins (flavin, pyridoxal phosphate, TPP), metal ions such as Fe, Zn, Cu, etc. |
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Michaelis-Menton Equation
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V₀= Vmax[S]/Km+[S]
- Most enzymes produce a hyperbolic curve for plot of V vs. [S] - Km = [S] required to reach Vmax/2; reflects the affinity for the substrate (lower Km, higher affinity) - Vmax = max rate of catalysis; catalysis if all available enzymes are saturated (depends on [E]) - Vmax/Km can vary depending on the presence of activators/inhibitors |
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Lineweaver-Burk plot
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- transformation of the Michaelis-Menton plot
- 1/V₀ = (Km/Vmax)(1/[S]) + 1/Vmax - produces linear graph of 1/V₀ vs. 1/[S] that is used to determine Km, Vmax from intercepts |
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Kinetic Constants
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- Vmax depends on amount of enzyme [Et]
- Kcat = Vmax/[Et] also referred to as turnover number - Kcat = moles product formed/s/mole of catalytic center - Unit of enzyme activity: μmoles product formed/min • Specific Activity: Units/mg protein |
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Utility of Enzyme kinetics
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- provides an estimate of biological activity of the enzyme.
- provides an estimate of the cellular concentration of metabolites (from determination of the Km value). - provides the basis for an accurate clinical determination of enzyme activity and desired metabolite levels in disease states - necessary for the characterization of inhibitors (which is most drug mechanisms) |
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Diagnostic procedures involving enzymes
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- Determination of levels of metabolites in blood. Ex: glucose (immobilized glucose oxidase), cholesterol (immobilized cholesterol oxidase) and triglycerides (immobilized lipase).
- Release of enzymes into circulation following tissue necrosis in disease states (must be fast turnover of tissue for enzyme release; isoforms can indicate location). Ex: myocardial infarction (creatine phosphokinase, lactate dehydrogenase), liver damage (lactate dehydrogenase, alanine aminotransferase). |
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Common Clinical Enzymes
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- Angiotensin Converting Enzyme (ACE) (Hypertension)
- Amylase (Pancreatitis) - Lipase (Pancreatitis) - Creatine Phosphokinase (CPK) (Myocardial lnfarc) - Alkaline Phosphatase (prostatitis) - Alanine Aminotransferase (ALT, SGPT) (Liver Diseases) - Aspartate Aminotransferase (AST, SGOT) (Myocardial lnfarc) - Gamma Glutamyl Transferase (GGT) (Myocardial lnfarc) - Creatine kinase 2 (CK2) (MI, peaks ~24hrs) - Lactate Dehydrogenase (LDH) (MI, peaks ~36-40 hrs; has liver and heart isofroms that can be recombinant) |
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Enzyme-Linked Immunoassays (ELIZA)
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- Marriage of enzymology with immunology
- Antibodies specific for a protein antigen is coupled to an enzyme such a horse radish peroxidase which allows detection of the antigen-antibody complex by the colored product of the peroxidase reaction. H202 + substrate → product that exhibits a color - Used in diagnostic tests for HIV |
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Toxins that target enzyme
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- compounds exert toxic effect by specifically binding covalently to an enzyme resulting in its inhibition (temp or permanent)
- e.g., organophosphates (pesticides and nerve gases) inhibit acetylcholine esterase. - e.g., aspirin binds to and covalently modifies cyclooxygenases I & 2 (CCXI & COX2). - Restoration of catalytic activity usually occurs only with synthesis of new enzyme (suicide modification) |
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Oxidoreductases
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- Catalyze oxidation-reduction reactions (electron transfer):
1. Dehydrogenases: SH2 → S 2. Oxidases: O2 → H2O2 3. Reductases: NADH + Sox → Sred + NAD+ 4. Peroxidases: H2O2 + Sred → Sox + H2O 5. Catalase: H2O2 → 02 + H2O 6. Oxygenases: S + O2 → SO + H2O 7. Hydroxylases: S + O2 → SOH + H2O |
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Amino transferases
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Transfer functional groups between donors and acceptors:
1. Transaminase: transfers a nitrogen from one substrate to another 2. Phosphotransferase: transfers a phosphate ester from one substrate to another 3. Kinase: transfers a phospho group from a high energy phosphate such as ATP to a substrate to form ADP and a phosphoester 4. Phosphomutase: transfers a phosphate ester from one OH group on a substrate molecule to another OH group on the same molecule (usually sugar phosphates) |
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Hydrolases
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Catalyze the cleavage of bonds by the addition of Water.
-CONH- + H2O → -COOH + -NH2 1. Proteases: Hydrolyze amide bonds in proteins 2. Lipases: Hydrolyze ester bonds in lipids 3. Phosphatases: Hydrolyze phosphoester bonds |
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Lyases
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Add or remove the elements such as water, ammonia, or carbon dioxide from/to a substrate molecule.
- Decarboxylases: R-CO2- → R-H + CO2 - Dehydratases: (Fumarate) -O2C-CH=CH-CO2- + H2O → (Malate) -O2C-CH-CHOH-CO2- |
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Isomerase and mutases
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- Heterogeneous group of enzymes.
Isomerases catalyze inversions at asymmetric carbons in substrates (ie. from D-amino acids to L-amino acids). - Also termed racemases and epimerases Mutases catalyze intramolecular transfer of groups such as phosphates from one site in the substrate to another. |
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Ligases
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- Ligate mean “to bind” and therefore this class of enzymes catalyze the joining of two molecules with the consumption of energy from an ATP
- Also referred to as "Synthetases" or "polymerases" - One important member of this class are the enzymes that catalyze the formation of aminoacyl tRNAs in the synthesis of proteins |
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Gluconeogenesis precursors
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- lactate/pyruvate (glycolysis products)
- amino acids (except leucine & lysine: ketogenic) - propionate (from odd chain/branched FAs) - glycerol (lypolysis of FAs) |
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Gluconeogenesis (general)
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- net synthesis of glucose from non-carbohydrate precursors (costs ATP)
- supplies glucose for dependent tissues: brain, RBCs, kidney medulla, lens, cornea, testis - responsible for ~64% of total body glucose during first 22hrs of fast and almost all by 46hrs - occurs when: glycogen stores are depleted (~12hrs); tissues temp. starved of O2 → excess pyruvate, lactate, alanine; amino acids or fats are catabolized for energy - 90% occurs in the liver, 10% in the kidneys |
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pyruvate carboxylase & PEP carboxykinase
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- bypass the pyruvate kinase step in glycolysis
- PCbase converts pyruvate to OAA (not rate limiting) uses ATP - PEPCK converts OAA to PEP (rate limiting, committed step) uses GTP - PEPCK is found in the liver and kidney but not the muscles (can't do gluconeo) so lactate must be circulated to the liver (Cori cycle) to be restored - activated by acetyl-CoA, cortisol, glucagon (increases transcription); inhibited by insulin |
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fructose 1,6-bisphosphatase
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- bypasses PFK-1 of glycolysis, converts F1,6,BP into F6P
- regulated by the same mechanisms as PFK-1 just in reverse: F1,6BPase is inhibited by insulin (via high F2,6BP concentration) and activated by glucagon; and inhibited allosterically by AMP, activated by ATP - found in the liver and kidney |
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glucose 6-phosphatase
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- bypasses hexokinase/glucokinase; converts G6P to glucose, freeing it from the cell
- Highest activity is in the liver (to supply other tissues with glucose), some kidney activity, little elsewhere (not found in muscle) - |
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Making glucose from different sources
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- Amino Acids: any glucogenic AA can be converted to an intermediate in the TCA cycle then to OAA + glycolysis (no leucine or lycine)
- Odd number FA's: after breakdown into acetyl-CoA (not glucogenic) 2C chain is converted to succinyl-CoA - Glycerol: converted to Gly3P then dihyroxyacetone phosphate, a glycolysis intermediate (btwn F1,6BP and G3P) (adiposites lack first enzyme/kinase) |
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Hormonal control of gluconeogenesis
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Glucagon: send glucose
- secreted into blood by α cells of pancreas - Promote: lipolysis of fat to deliver fatty acids to the liver - Promotes gluconeogenesis in the liver by inducing expression of PEPCK and inactivation of PyrK by phos - Other steps to promote gluconeogenesis Insulin: use glucose - Secreted into blood by β cells of pancreas - Promotes transport of glucose from the blood into cells - Represses lipolysis of fat - Induces expression of glucokinase, PFK- 1 and PyrK - Stimulates glycogen synthesis in liver and muscle - Other steps to limit gluconeogenesis ---In diabetics, the rate of hepatic gluconeogenesis is 3-times the normal! (so drugs target PEPCK) |
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Glycogen storage
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- Most stored in the liver as granules (available for export (for the brain). <10% of wet weight
- Muscles store for local use: <1-2% - stored content oscillates throughout the day based on eating patterns (fulls storage last ~12hrs) - can be mobilized quickly (unlike fat) w/o O2, not osmotically active like glucose |
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Properties of sugars
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- occur in linear (has C=O) and cyclized forms.
- glucose C1 carbon = anomeric carbon. α form: OH down, 36%; β: OH up (axial), 64% (we can't digest cellulose b/c uses β 1-4 linkages) - sugars with a free anomeric oxygen can reduce Cu/Fe ions (was used to diagnose diabetes, now use glucose oxidase) |
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Glycogen general
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- linear α1-4 linkage, branching α1-6 linkages all via dehydration.
- assembled and degraded at the non-reducing ends (branched to maximize speed and solubility) only one reducing end w/ a glycogenin molecule - Gluconeogenesis: net synthesis of glucose from noncarbohydrate sources (AA's, lactate, pyruvate, propionate, glycerol). Distinct from glycogenolysis, which i cleaving glucose from glycogen storage. |
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Glycogen synthesis
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Initiation: glycogenin self glycosulates w/ 8 UDP-glucose → primed glycogenin allows GlySyn action
- Extension: Glucose →(HexK+ATP)→ G6P →(phosGmutase)→ G1P →(G1P urydylyltransferase +UTP)→ UDP-glucose →(GlySyn)→ glycogen(n+1) + UDP - Branching: branching enzyme (bi-functional) cleaves terminal 6-8C chain, transfers to 6C of other chain |
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Glycogen degradation
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- shortening: glycogen phosphorylase cleaves with PO4 at the reducing ends, leaving G1P which can then be converted to G6P via mutase (and released in liver by G6Pase). Can't get within 4 residues of a branch
- debranching: 4-D-glucotransferase cleaves 3 residues and transfer to end of straight chain. A-1,6-glucosidase cleaves remaining G1P |
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Glycogen regulation
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- Glucagon and β-agonists stimulate (Epi) cAMP medicated glycogen degradation, by activating GlyPlase and inhibiting GlySase & glycolysis in liver.
- α agonists (Epi) trigger degradation by activating phospholipase C, activating diacylglycerol and Ca+ release from ER activating PKA(liver)/PKC (muscle) which inhibit GlySase (Ca+ also activate GlyPlase) - insulin stimulates synthesis by kinase mediated signaling which activates GlySyn and inhibits GlyPlase (in muscle also activates GLUT4, increasing Glu in cell to polymerize) |
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Glycogen Storage diseases
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- Von Gierke's: defective G6Pase preventing Glu release from the liver
- Pompe's: α-1,4-glucosidase (H2O cleavage); prevents cleavage of glycogen in the lysosomes (granule accumulate) - McArdle's: muscle phosphorylase, prevents degradation in muscle, muscle weakness, cramps, low lactate |
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Fructose consumption
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- 6C sugar (5 point ring)
- 4000% consumption increase 1970-2000, decrease normal sugar - fructose has lower glycemic index (less Glu in blood), but is more readily converted to fat so thought to contribute to obesity and insulin resistance - rapidly converted to F6P (glycolysis in muscle bypassing HexK) - in liver easily converted to F1P, then broken down to glyceraldehyde & dyhydroxyacteone bypassing PFK-1 (rate limiting step) going to glycolysis or FA synthesis - defects in fructokinase or F1P aldolase lead to fructosuria/fructose intolerance |
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Galactose metabolism
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- 6C sugar with flipped OH on C4
- Gal →(GalK)→ Gal1P then Gal1P + UDP-Glucose → G1P + UDP-Gal via gal1P uridylyltransferase (epimerase then converts UDP-Gly to UDP-Glu) -Defects in Gal1P-UT (or other pathway enzymes) cause galactosemia (milk intolerance), where Gal1P builds up and causes brain defects |
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Mannose metabolism
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- 6C sugar with flipped OH on C2
- Man →(HexK)→ Man6P →(PhosMan Isomerase)→ F6P → then into the glycolysis pathways |
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Pentose phosphate pathway
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- reduces glucose anaerobically, produces 2NADPH but no ATP (6C → 1+5C)
G6P →→6-phosphogluconate → Ribulose 5-phosphate → lots of isomerases can convert this to glycolysis intermediates - G6P DH deficiency (X-linked): first step in process; causes loss of NADPH production → loss of glutathione antioxidant system→ increase ROS stress→ membrane damage→ RBC lysis (hemolytic anemia: precipitated by oxidants, diet, infection) - confers selective advantage against malarial infection in female carriers |
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Overall protein metabolism & free amino acid/Nitrogen pool
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- used to make: new protein (equal to the amount broken down, ~400g/d), energy (not favored): glucose, FA's, ketone bodies; other molecules: porphyrins, creatine, neurotransmitters, de novo synthesis of nucleic bases, other N compounds
- Comes from degraded cellular protein, dietary protein (stomach pepsin/HCL & pancreas enzymes break down to digestible pieces), new synthesis - AA's are not stored: made/absorbed then used/degraded. Turnover is roughly constant: nitrogen balance |
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Waste products of Nitrogen metabolism
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- creatinine: from the breakdown of creatine phosphate in muscle, excreted in urine.
- CO2 + H2O: from keto-acids/AA C skeleton → carbs/FA's/TCA cycle, excreted through lungs & urine. - bilirubin: from porphyrins/heme; excreted in feces. - Urea: from urea cycle (carbamyl phosphate), urine - NH4: from pyrmidines, free NH4, urine - uric acid: from purines, urine |
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Blood urea nitrogen (BUN)
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- normally little free ammonia in the blood or urine (toxic). In blood most N is non-protein, then urea, in urine most is urea
- Urea normally will be excreted in urine, unless pathological causes - BUN increase: kidney problems, high protein intake (more liver load) or muscle abnormalities, other diseases (gout, Heart failure, rheumatoid arthritis) - BUN decrease: liver dysfunction, low protein intake, infections (interfere w/ urea cycle), intestinal malabsorption (Celiac) |
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Nitrogen transport/ organ specific excretion
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- NH3 produced by all tissues during metabolism (amino acids), free NH3 is toxic to brain (pH imbalance, crosses BBB, neurotransmitter (glutamine) imbalance); will increase if defects in liver/urea cycle/mitchondria/energy metabolism
- transported in blood to liver or kidney for excretion via amino acids: glutamine or alanine depending on tissue. - brain removes ammonia by binding in glutamine and glutamine (via glutamate DH & glutamine synthase - Kidney and liver reverse to free NH3 from glutamate/glutamine (+ alanine in liver). Then excrete or used in urea cycle - skeletal muscle uses alanine from pyruvate, transported to the liver |
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Removal of nitrogen from amino acids
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- AA's can't degraded until α-amino group is removed. Accomlished by transamination (and reversed by oxidative deamination (glutamate only))
- amino group is transfered to αKG via aminotransferase (+NADPH) producing glutamate and α-keto acid (except AST which forms aspartate from OAA) (in most tissue use glutamate DH) - amino is freed from glutamate by GDH in oxidative deamination. - GDH is allosterically regulated: forward coenzyme: NAD+, reverse is NADPH. Overall activated by ADP (use AA skeleton for metab), inactivated by GTP |
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Key points of urea cycle
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- Glutamate → αkg releaseing NH3 (via glut DH)
- NH3 + CO2 + 2ATP → carbamoyl phosphate (via CPS1,N-acetylglutamate dependent [via NAG synthase], rate limiting step) - Carbamoyl phosphate + ornithine → citrulline (transported out of mito) - Citrulline + aspartate → [arginosuccinate]→ arginine + fumerate (recycled to OAA and aspartate via glut DH) - arginine → urea + ornithine (transported back into mito) |
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Urea cycle disorders
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CPS or NAGS defect: lack of synthesis of carbamoyl phosphate → build up of NH3 → hyperammonenia
ornithine transcarbamolase defect (X-recessive): build up of CP (and NH3) which spills to cytoplasm (where CP2 is also making it) → increase orotic acid (pyrimidine synthesis intermediate) → orotic aciduria argininosuccinate syntate defect: build up of citrilline (and NH3, smaller) → citrullinemia (detectable in blood) Arginosuccinate lyase defect: buildup of argininosuccinate → argininosuccinic aciduria (in blood and urine) Arginase defect: increase arginine, secreted in urine ornithine transporter defect: buildup of ornithine outside and CP inside mito therefore NH3 buildup → orotic aciduria, hyperammonemia - All are autosomal recessive except OTC (X-recessive) - treatment: restrict diet (low protein), supplement of AA formulas/intermediates (arginine), medications (ammonium scavengers: Na-Benzoate, phenylbutyrate) |
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General amino acids
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- 20 natural AA's are used for protein synthesis (encoded by codons)
- essential AA's are not synthesized, must be obtained in diet - methionine, and phenylalanine are not used in proteins but are used in synthesis of tyrosine and cysteine; arginine is cleaved to form urea - Also classified as glucogenic (AA's that catabolized to pyruvate or TCA intermediate) or ketogenic (yield acetoacetate or precursor). Only Leu, Lys are ketogenic; Tyr, Iso, Phe, Trp are both. - used to synthesize many compounds including porphryns (heme, bilirubin), catecholamines, histimine, serotonin, creatine, melanin, (may also act directly as neurotransmitters) |
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Amino acid catabolism
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- first step is transfer of N group to αKG producing a keto acid and glutamate via an amino transferase (NH3 then released in liver/kidney by GDH, and C-skeleton degraded in TCA or as acetyl-CoA)
- all AT's require pyridoxal phosphate as a cofactor (derivative of VitB6) - amino transferases are specific to only 1/few AA's. (lysine and threonine don't use deaminases instead). - High plasma AT's indicates tissue damage (found in most cells, esp. liver, kindey, intestine, muscle): ALT (alanine AT) peaks ~36hrs after toxic ingestion (followed by bilirubin increase) (amanita phalloides); AST: spikes 6-8 hrs after MI (also high in liver/pancreas damage) - Branched AA's (Iso, Leu, Val) undergo transamination, Ox. decarbox, FAD-linked dehyrdrogenation |
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S-adenosylmethionine (SAM)
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- formed by catabolism of methionine with ATP (via SAM synthase)
- SAM is the major methyl-group donor in one carbon metabolism (irreversible) - Converted to SAH (toxic) after donating methylgroup then homocysteine, which can be converted to cysteine or tetrahydrofolate + methionine (via methyltetrahydrofolate). Defect in homocysteine metabolism is risk factor for heart disease, lens dislocation, osteoporosis, retardation - important in energy storage (creatine synthesis), cell proliferation, DNA methylation (M-cystidine, M-adenosine), FA oxidation (carnitine formation), hormones & neurotransmitter production (Epi for NE) |
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Synthesis of non-essential amino acids
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- Ala, Asp, Glu formed by transamination of keto-acids. (pyr, OAA, αKG respectively) (N from another AA)
- Gln, Asn formed by amidation of Glu, Asp - Pro formed by cyclization and reduction of Glu - Ser oxidized/transaminated from 3PG (glycolysis intermediate). Gly and Cys (w/ Met) formed from Ser - Tyr formed from Phe (essential AA) |
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Phenylketonuria
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- deficiency of phenylalanine hydroxylase preventing Tyr synthesis, and accumulating Phe
- most common inborn error of AA metabolism. May also be caused by other errors: failure to restore BH4 (coenzyme) from BH2 (BH4 reductase) (would also cause decreased catecholamine and serotonin synthesis b/c BH4 is required) - Characteristics: elevated Phe everywhere (Phe ketone in urine), CNS symptoms (retardation, seizures, motor difficulties, others), hypopigmentation (hydroxylation of tyrosine to form melanin inhibited by high Phe) - now screen in neonates - treated by diet (+ possible BH4 replacement) |
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Maple syrup urine disease
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- rare, autosomal recessive; complete or partial deficiency in branched-chain α-keto acid dehydrogenase (BCKD) (decarboxylates Leu, Iso, Val)
- branched amino acids and keto acids accumulate in blood --toxic to brain - charaterized by: sweet smelling urine, severe metabolic acidosis, retardation, disabilities, death - screened in neonates - treated with synthetic diet low in branched AAs (rare thiamine dependent from can respond to supplementation) |
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Examples of glycine metabolism
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– simplest amino acid (variable group R=H)
- involved in synthesis of protein, glutathione, porphyrins, purines, creatine, THF (spilt to CO2 + NH4 + C1 in liver mito) - important in the control of gluconeogenesis (can be converted to pyruvate via serine) and neurotransmission pathway (is a neuro-inhibitory neurotransmitter) - Nonketotic hyperglycinemia: characterized by mental retardation and accumulation of Gly in body fluids esp CSF; only in Finland |
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Folic Acid in amino acid metabolism
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- able to donate C1, part of the "one-carbon pool"
- produced from folatic acid (vitamin) by dihydrofolate reductase to active form THF (carbon bound to N5 or N10 or both) - involved in reducing homocysteine, formation of RBCs, protein metabolism, cell growth/division (esp DNA synthesis {dTMP, dUMP}, repair, methylation) - lack of folate can result in spina bifida |
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dihydrobiopterin reductase
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- reduces dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4) using NADH (preferred) or NADPH
- if deficient can cause phenylketonuria and decreased neurotransmitter synthesis - BH4 is a required cofactor in the conversion of phenylalanine to tyrosine, chatecholamine production from tyrosine, and serotonin production from tryptophan |
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Catecholamine synthesis
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- biogenic amines: dopamine, norepinephrine & epinephrine.
- Synthesized step-wise from Tyr in reactions dependent on: BH4, PLP (B6), vitamin C, and SAM. - Dopamine, norepinephrine in brain = neurotransmitters - Norepinephrine/ epinephrine outside CNS = hormones regulating carbohydrate and lipid metabolism. - Parkinson’s disease = neurodegenerative movement disorder resulting from idiopathic loss of dopamine producing cells (treated with L-DOPA) |
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Creatine synthesis
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- synthesized from Gly, Arg, Met in the kidney and liver, converted to phosphocreatine in muscle (stores energy) via creatine kinase. Excreted as creatinine in urine (after de-phos'd)
~half of the daily creatine is biosynthesized, rest is taken in by alimentary sources. - Ninety-five percent of creatine is stored in the skeletal muscles; also significant in heart. Creatinine content of urine proportional to total creatine phosphate => can be used to estimate muscle mass - Presence of creatine kinase (MB isozyme) – diagnostic of myocardial infarction) |
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Biological functions of nucleotides
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- Energy metabolism: ATP synthesis
- information: role as subunits of DNA, RNA - physiological mediators: cAMP, cGMP are 2nd messengers - Components of coenzymes: NAD, FAD, NADP, Coenzyme A - Activated intermediates: for small molecule group transfer (lipids, carbs, methyl, sulfur). Ex: SAM (methyl), PhosAdenosine PhosSulfate (sulfur), CDP-choline/ethanolamine (Lipid) - allosteric effectors: binding to enzymes and regulating their activity |
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General nucleic acids
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- pyrimidines CUT (6C ring w/ N1,3, =O C2, variable C4,5), purines HAGX (C6+5 rings w/ N1,3,7,9, variable C2,6)
- nucleoside (-sine) = base + sugar; nucleotide (-ylate) = base + sugar +phosphate [hypoxanthine → inosine/inosinate] - deoxynucleotides are missing the 2' OH on the sugar, usually very low [ ] except during S phase, when reductase converts NDP → dNDP (recycling of equivalents keeps this process going) |
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Creation of new nucleotides
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De novo: assembly of new nucleotides from small building blocks: single carbon, nitrogen donors, amino acids, sugar-phosphates. Very energetically costly, done more in lymphocytes
Salvage: intact bases put on sugar-phosphates. Done more in brain. Accomplished by Base-PRPP trasnferases - 5-phosphoribosyl-1-pyrophosphate (PRPP) is an activated sugar (from ribose 5-phosphate) that connects sugar metabolism to nucleotide metabolism |
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De novo purine synthesis
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- requires: glycine + NH from glutamine + NH from aspartate + C1 from THF + CO2
- purine ring is synthesized stepwise (10) by ATP hydrolysis on the phosphate sugar - all enzymes are cytosolic - First step/enzyme: glutamine-PRPP amidotransferase (transfers N to sugar) is rate limiting/committed step - process generates IMP → AMP or XMP (→ GMP) - regulated by feedback inhibition from IMP, AMP, GMP, activation by PRPP |
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De novo pyrimidine synthesis
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- RXN: NH from glutamine + CO2 + ATP →Carbamoyl phosphate + aspartate → close ring via oxidation in the mitochondria. → orotic
- ring synthesized then added to PRPP - OMP is decarboxylated to UMP, UTP nitrogenated by glutamine to CTP - formation of carbamoyl phosphate by CPSII is rate limiting (not commited). Inhibited by CTP, UTP - TMP formed from dUTP by thymidulate synthesis (uses THF to donate methyl) |
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Degradation of purines
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Process: nucleic acids → nucleotides → nucleosides → oxidized purines (don't break ring)+ phosphorylated sugars + free NH4. End in xanthine which can be converted to uric acid (accumulates in Gout, treated by allopurinol which inhibits xanthine oxidase)
- adenosine deaminase deficiency: reduced adenosine → inosine conversion, severe combined immunodeficiency (B & T cells), bubble-boy syndrome; adenosine builds up in lymphocytes as dATP inhibiting ribonucleotide reductase activity, preventing lymphocyte proliferation and immune response - purine nucleoside phosphorylase deficiency: (removes sugar from G, H) T-cell immunodeficiency due to accumulated dGTP and DITP which inhibit proliferation |
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Degradation of pyrimidines
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- process: nucleases remove P, then NH4 removed, then phosphorylated sugar, leaving U & T which are broken open to β-alanine and β-aminoisobutyrate. (isoaminoacid derivatives) (if found in blood indicates tissue damage/turnover)
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Compounds that interfere with nucleotide metabolism
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Base/nucleotid analogs (anti-metabolites) (cancer drugs)
- 6-MP (inhibits IMP→AMP/GMP), 5-fluorouracil (as F-UTP, F-UMP inhibits RNA processing & TMP synthesis), cytosine arabinoside (inhibits DNA polymerases) Anti-folates (interfere w/ folate reduction/activation) - methotrexate (targets dihydrofolate reductase, irreversibly binds inhibits new nucleotide synthesis) Nucleoside inhibitors of virus replication - acyclovir (terminates DNA polymerization when incorporated--Herpes kinase better at phosphorylating than human so selective for virus) - 3'-azido-3'deoxythymidine- treats HIV, viral reverse transcriptase uses as a chain terminator |
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Lesch-Nyhan syndrome
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- significantly low HGPRT (adds purine to PRPP in base salvage); inability to salvage hypoxanthine or guanine
- Brain is reliant on salvage for nucleotide synthesis so toxic metabolites accumulate there - un-uses PRPP drives de novo purine synthesis (makes it worse), unused xanthine → uric acid → hyperuricemia, gout - causes mental retardation, self mutilation, other neurological squelae. - rare X-linked |
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Proteins that use iron for functional activity or storage/transport
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Heme iron proteins:
- hemoglobin (circulating form), myoglobin (storage form), cytochrome P450 enzymes & other cytochromes (involved in xenbiotic metabolism--getting rid of drugs, ETC), cytochrome oxidase, peroxidases (accept/donate e- to ROS), catalases Non-heme proteins (a.k.a. iron-sulfur proteins) - succinate dehydrogenase (TCA, ETC CII), aconitase (TCA), NADH dehydrogenase (ETC CI), adrenodoxin, cytochrome c reductase, ribonucleotide reductase, acyl coenzyme A dehydrogenase, xanthine oxidase Proteins that use Fe for storage/transport - transferrin (Tf) & transferrin receptor (TfR) (transports iron in blood, no free Fe, receptor takes up iron and transporter) - ferritin, hemosiderin (store Fe in the cell, hemosiderin is a denatured, inactive storage form) - lactoferrin (binds Fe in breast milk to transfer to the baby) |
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General biological Iron facts
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- All living cells require iron.
- Iron is abundant and is redox active. - Iron exists mainly in the form of insoluble oxides, yet living systems must provide it in a readily available, soluble form, that can be transported throughout the body. - Living systems contain large amounts of iron, but only small amounts are absorbed and excreted daily (<1-2mg). - Iron can be extremely toxic. |
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Fenton process
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- mechanism of iron toxicity with ROS
- Ferric iron (Fe3+) reacts with O₂-• → O₂ + Fe2+ (Ferrous). Ferrous iron then reacts with H₂O₂ → Fe3 + HO• (which can not be safely dealt with → toxicity - Overall: O₂-• + H₂O₂ → O₂ + H₂O + HO• (mediated by Fe, worse than starting products because they can be safely detoxified but radical product cannot) |
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Iron and the diet
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- Dietary iron is closely linked to caloric intake (amount absorbed depends on amount consumed): 6-7 mg iron/1000 calories
- Only a small portion of dietary iron is absorbed, and varies with composition of the diet. - Non-heme iron is the main source of dietary iron; heme iron contributes only 1-2 mg/day (preferentially absorb heme-iron, but just not that much in diet) |
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Iron homeostasis
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- 4 main "pools" of iron: tissue (500mg), stores (1000mg), free/transferrin (3 mg), RBCs (2300mg) [in a 70kg man].
- Total iron in the body: 3800mg, daily flux between these: 20-30mg (<1-2mg absorbed/excreted per day) - Functional forms (hemeoglobin, myoglobin, heme/non-heme enzymes) account for 74% of total iron - Storage forms: ferritin (active) and hemosidern (inactive) so the remaining 16% (almost entirely in tissue) - the plasma iron pool is recirculated between the tissues and allows for flux between the pools (RBC destruction → RBC production → RBC use...) |
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Iron Absorption
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- About 1 mg/day is required in healthy males (can increase 4-5 fold in menstruating women) - Absorption by the duodenal enterocytes is influenced by: amount in the diet, composition of the diet, form of iron (heme/non-heme), inhibitors/activators of absorption
- Only ~10% of dietary iron consumed is absorbed - Absorption is enhanced by ascorbate, citrate and gastroferrin (bind the metal ions). It is inhibited by phosphate, oxalates, tannins and phytates - intestinal cells self regulate absorption: Immature cells develop in cypts and get Fe from plasma transferrin (mediated by TfR1 and HFE protein (restrictive)). When mature cells migrate to villi they are then programmed to absorb small amounts of Fe (via divalent metal transporter (DMT1) and transfer to ECF by Ferroportin, excess is stored as Ferritin) |
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Uptake and recycling of transferrin
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- each Tf has binding sites for 2 Fe (can bind 1 or both)
- iron-loaded Tf binds to TfR, clathrin coated pits then vesicles form. Vesicles develop into endosomes, low pH dissociates the Fe from Tf which is released in the cell (to ferritin). The vesicle recycles Tf/TfR to the PM where they dissociate - only a small amount of Tf (binds ~3mg Fe) - TfR translation is reciprocally (vs. ferritin) regulated by cytosolic aconitase (low Fe binding increases translation, opposite of ferritin) |
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Ferritin structure and function
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- ferritin is a large multidimer (24 subunits) with both H (heavy) and L (light) chain subunits (not that much difference). Form a apoferritin shell that accepts Fe2+ iron from transferrin and stores at as Fe3+ in a central iron crystal
- translation is reciprocally regulated by cytosolic aconitase (in low Fe, binding reduces translation, opposite of TfR |
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Aconitase
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- is an iron response element (IRE) binding protein found in cytosol (different than TCA aconitase)
- active form binds iron, doesn't bind an IRE; inactive form is iron fee and can bind to an IRE sequence to change [Fe] - in low [Fe], iron-free aconitase binds to the 5'UTR of ferritin mRNA, preventing the ribosome from translating the protein; also binds to the 3'UTR loop of TfR mRNA which stabilizes and prevents it from being degraded (normally degraded from 3' end) so more TfR is produced. --In low [Fe] aconitase binding reduces storage and increases Fe influx into the cell by post-transcriptional regulation. In high [Fe] aconitase binds Fe instead, so ferritin is made and TfR is less |
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Measuring Total Iron Binding Capacity
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- effectively measuring the % saturation of transferrin (normall pretty low) --iron status of the patient
- take 2 blood samples, add known amount of free iron to one (will saturate Tf) and G-HCl to the other (will dissociate all abound Fe). Add color to both to find the [Fe] in each - Unused IBC = iron added -free iron measure (in Sol'n 1) - Total IBC = Serum iron (in sol'n 2) + UIBC (above) (normal: 240-450 μg/dL) % Saturation = serum iron/ TIBC (normal: 20-50%) |
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Iron deficiency causes and diagnostics
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-most prevalent nutritional disorder
Causes - Blood loss (menses & pathologic conditions of GI tract (e.g. colon cancer)) - Inadequate dietary intake - Malabsorption of iron - Increased need for iron: pregnancy Diagnostics - low serum iron - high TIBC (total iron binding capacity) - low % saturation of Tf - low serum ferritin (as a result of cell death) - bone marrow aspiration and staining of macrophages for iron is negative |
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Iron-overload states
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Hereditary Hemochromatosis (HC)
- Abnormally high absorption over many years (intestinal mucosa lose capacity to limit iron intake). Results in iron accumulation in and failure of liver, heart, pancreas - Autosomal recessive (incidence —11300), due to mutations in HFE (**see below), HJV, HAMP, TfR2 or Ferroportin (dominant) (these normally restrict iron intake) - Diagnostics: High serum iron, Low or normal TIBC (liver toxicity reduces synthesis), High % saturation, High serum ferritin, Liver biopsyiiron stain - Treatment- phlebotomy (most Fe is in RBC so this gets rid of it) Transfusion overload - Occurs due to frequent transfusions secondary to chronic hemolytic anemia (e.g. sickle cell) - Treatment IV administration of iron-chelator Models for HFE mediated hemochromatosis - development: mutant HFE restricts Fe influx during development making mature cells hyperactive luminal Fe absorbers - hormone mediated: HFE controls synthesis of hepcidin (peptide hormone made in liver) which slows iron release from ferroportin. Mutant HFE reduces hepcidin production, allowing uncontrolled Fe release from enterocytes and macrophages |
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Zinc
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- biological uses: immune system, cell growth/division, wound healing, taste and smell
- RDA: 12-15 mg/day - Dietary sources: high protein foods (dark meat, fish, dairy, legumes), NOT fruits/veggies - Zn deficiency: more common in vegetarians, symptoms include slow growth, poor appetite, impaired smell/taste, hair loss - Zn overload: toxicity results in abdominal cramping, diarrhea, vomiting |
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Selenium
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- Biological uses: enzyme function (especially antioxidants, glutathione peroxidase), production of antibodies after vaccination, make fertility
- RDA: 50-200 μg/day (often in supplements, though American diet is usually sufficient) - Sources: fish, red meat, chicken, grains, eggs, garlic, yeast - Se deficiencies: may occur in people fed by IV for long time, (otherwise rare) - Se toxicity: also rare may cause tooth, nail and hair loss, skin inflammation |
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Energy and protein metabolism during starvation and nutritional repletion
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During starvation: ↓plasma glucose, AA, TAG → ↓insulin, ↑glucagon; TAG, glycogen, protein are degraded for energy. Main priorities: 1. Maintain adequate glucose in glucose-requiring tissues (brain, peripheral nerves, RBC, WBC, bone marrow, and renal medulla). 2. Mobilize free FA's from adipose & synthesis/release of ketone bodies by liver to supply energy to all other tissues
- Pancreas: ↓insulin, ↑ secretion [opposite in replete state] - Adipose: TAG breakdown releasing FA + glycerol for peripheral fuel & gluconeo. [Well-fed: synthesize/store TAGs, glucose uptake] - Skeletal muscle: adapts to use ketones & FA for fuel; ↑ protein breakdown to provide AA's for gluconeo. [WF: glucose uptake, glycogen & protein synthesis] - Liver: ↑glycogen breakdown & ↑gluconeo; uses FA Ox. for energy; synthesizes/releases ketones [WF: synthesis of glycogen, FAs, TAGs, VLDL] - Brain: adapts to primarily use ketone bodies (from the liver) [WF: only uses glucose] |
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Key elements of nutritional assessment in adults
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1. Review of past medical-surgical history and history/tempo of current illness (degree of catabolic stress, organ function, medications, IV/electrolite therapy, upcoming procedures)
2. Physical examination (muscle wastine, fat stores, wounds, organ dysfunction, dehydration) 3. Body weight history (healthy vs current, calculate BMI, weight loss, current weight as % of ideal) 4. Dietary intake pattern (changes recently, unusual/excessive consumption, enteral/IV support) 5. Gastrointestinal tract function 6. Functional status 7. Biochemical tests in blood (electrolytes, BG, organ function tests, selected specific nutrients) 8. Estimate energy (calorie), protein and micronutrient needs (calculate basal energy expenditure) 9. Enteral/parenteral access for nutrient delivery |
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Major causes of malnutrition
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- Decreased nutrient intake: anorexia, GI problems, emotional stress, lack of food ( famine), food is withheld (upcoming surgery).
- Abnormal nutrient losses: wounds, drainage tubes, renal dialysis, diarrhea, emesis, and polyuria. (Nutrients essentially lost through any major loss of body fluid). - Increased nutrient needs- physical stress from infection, trauma, burns, etc. - Decreased physical activity- physically inactive patients (i.e. bed rest) have decreased protein synthesis and physical wasting |
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Major consequences of malnutrition
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- Increased catabolic hormones and cytokines: increase in glucagon and cortisol hormones contributes to the metabolic changes. Cytokines are catabolic, so they contribute to protein breakdown.
- Resistance to anabolic hormones (insulin) - Decreased blood levels of anabolic hormones (testosterone) - Decreased substrate utilization: lower glucose and amino acid uptake - Skeletal muscle weakness: due to loss of calories or decreased protein synthesis - Increased rate of infection - Impaired wound healing: can result from various deficiencies including calories, protein, vit C, vit A, zinc, other micronutrients - Prolonged convalescence: slower recovery as the body has less ability to regenerate tissue - For children, additional consequences include delayed development, increased risk of infections, and other chronic diseases |
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Enteral and parenteral nutrition support strategies
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Enteral Feeding: food + complete oral supplements (can be NG or G tube)
-Benefits: enhances gut mucosal integrity, maintains absorptive functions, enhanced gut-associated immune functions, decreased bacterial translocation Parenteral feeding: complete intravenous nutrition (bypasses GI tract completely, best for patients with GI problems). Can be standard, hydrolized (pre-digested), or immune enhancing (contains immune-modulating nutrients) |
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Clinical manifestations of nutrient deficiencies
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Marasmus: total nutrient deficiency
Kwashiokor: protein deficiency, adequate calories Rickets: Vit D deficiency (bowed legs) Pellagra: niacin deficiency (brownish rash on sun-exposed skin. 4 D's diarrhea, dermatitis, dementia, death) Glossitis: deficiencies in folate, B12, thiamine, riboflavin, niacin, and/or iron (discolored, smooth, painful tongue) Petechia: Vit C deficiency (broken capillary vessels) Mouth/nose lesions: zinc deficiency Cheliosis/angular stomatitis: deficiencies in riboflavin, niacin, folate, and/or B12 (lip fissures)(often in Short bowel) |
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Clinical manifestations of nutrient deficiencies
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Marasmus: total nutrient deficiency
Kwashiokor: protein deficiency, adequate calories Rickets: Vit D deficiency (bowed legs) Pellagra: niacin deficiency (brownish rash on sun-exposed skin. 4 D's diarrhea, dermatitis, dementia, death) Glossitis: deficiencies in folate, B12, thiamine, riboflavin, niacin, and/or iron (discolored, smooth, painful tongue) Petechia: Vit C deficiency (broken capillary vessels) Mouth/nose lesions: zinc deficiency Cheliosis/angular stomatitis: deficiencies in riboflavin, niacin, folate, and/or B12 (lip fissures)(often in Short bowel) |
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Lipid uses
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Energy storage: provide long term storage of energy that is more efficient and dense that carbs
- TAGs (synthesized from FA's) have a much greater energy density (9 kcal/g) that carbs (4kcal/g) or proteins (4kcal/g) and does not require water (so less volume/density). The disadvantage is that energy cannot be rapidly stored or accessed. Membranes: major building blocks of biological membranes, including phospholipids, sphingolipids, glycolipids, cholesterols |
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Fatty acids
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- long hydrocarbon chains of varying number methylene groups with terminating carboxyl group at one end (methyl on the other).
General formula: CH₃--(CH₂)n--COOH - carbons are counted at the carboxyl end (carboxyl, alpha, beta...). Nomeclature: #C:#C=C - Palmitic acid (16:0) is made by FA synthase then modified to other FAs (all can be made except double bonds w/in 7 bonds from the methyl end) - unsaturated FAs are common (up to 6/chain), always in cis configuration. - 3 FA's bound to glycerol to store energy as TAGs - broken down in 2C units--beta oxidation |
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Acetyl-CoA in lipid metabolism
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- acetyl-CoA is the precursor for FA's/TAGs, cholesterol, ketone bodies. Any molecule that can be broken down to acetyl-CoA can be used to synthesize FA's
- FA synthesis occurs entirely in the cytoplasm, but ACoA gets produce in mito (where pyr DD and AA breakdown enzymes are), so binds w/ OAA and leaves as citrate (then restored in cyto by ATP-citrate lyase). OAA in cytosol is converted Malate/pyruvate releasing NADPH needed for FA synthesis - added to carboxyl end of growing FA via FA synthase |
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Fatty acid synthesis (general)
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- series of reactions all catalyzed by Fatty Acid synthase (large polypepide w/ multiple activites, somwhat similar to a ribosome)
- FA's synthesized by sequential addition of 2C units to the activated carboxyl end, using NADPH for energy. - saturated, straight chain palmitic acid (16:0) us synthesized first then modified to other FAs. - Formation of Malonyl CoA from acteyl-CoA and bicarbonate (+ATP) via acetyl-CoA carboxylase is the commited and regulated step (allosterically activated by citrate to form active polymer from inactive dimers and inhibited by long-chain fatty acyl-CoA; globally activated by insulin (dephosphorylated by PP1), inhibited by glucagon (phosphorylated by cAMP)) |
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Fatty Acid synthase (and steps)
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1. Condensation
- acyl carrier protein (ACP) domain, binds ACoA, transfers it to cysteine residue, ACP binds MCoA, MCoA attacks ACoA losing CO2 2. Reduction - tail end ketone group is reduced to alcohol by NADPH 3. Dehydration - water is removed creating an omega-2 double bond 4. Reduction - double bond is reduced by NADPH, producing butyryl-ACP (4C FA at ACP) [growing FA is then transfered to cysteine group, new MCoA is bound and enlongation continues] - Upon completion of synthesis, thioesterase releases palmitic acid from FA synthase (in breast milk thioesterase has different specificity so cleaves earlier, making shorter, digestible FA's) - FA synthase expression is induced by insulin and suppressed by mono/polyunsaturated FA's in the diet |
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Palmitate as the precursor of other fatty acids
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- other FAs are produced from palmate through:
Elongation: 1. occurs in endoplasmic reticulum (ER) or mitochondria 2. in ER uses malonyl CoA as substrate 3. most tissues convert palmitate into stearate exclusively 4. brain contains additional elongation systems to produce longer FAs (also use malonyl CoA) 5. mitochondrial elongation systems use ACoA instead of MCoA Desaturation: - occurs at multiple locations, with different desaturases based on location (none for last 8Cs) - stearoyl-CoA destaturases: plases initial C9/10 double bond, then other double bonds can be introduced - Polyunsaturated fatty acids (PUFAs) are formed by both elongation and desaturation |
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Storage of Fatty Acids as triacylglycerol
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- Liver and adipose tissue (and to a lesser extent, most body tissues) convert FAs to TAGs
- Adipose is specialized for synthesis, storage, and hydrolysis of TAGs - TAGs are the main system for long-term energy storage in humans and most FAs in humans occur as TAGs - In TAG all three hydroxyl groups on glycerol are esterified with a fatty acid; rarely are the FAs the same in three positions; usually is a complex mixture - TAG yields nearly 2.5X the ATP on complete oxidation than glycogen - TAG is stored without associate water (glycogen binds twice its weight in water when stored); thus, equivalent amount of energy from glycogen weighs more than TAG |
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TAG synthesis/hydrolysis
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Synthesis
1. glycerol is converted to glycerol-phosphate via glycerol kinase 2. Acyltransferases add 2 FAs to form phosphatidic acid 3. Phosphatidic acid broken down to diacylglycerol by phosphatase 4. 3rd FA is added by acyltransferase forming the TAG Hydrolysis: - glucagon or epinephrin stimulation activates hormone-sensitive lipase (by cAMP phosphorylation) which cleaves FA's from TAG [opposite regulation of lipoprotein lipase which cleaves FA's from TAG in chylomicrons facilitating absorption) - FAs are then bound to albumin for transport and glucagon used for gluconeo |
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Transport of FAs into the mitochondria for β-oxidation
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1. Fatty acids are converted to fatty acyl-CoA by acyl-CoA synthetase
2. FA-CoA is bound to carnitine (by carnitine palmitate transferase, CPTI) forming acylcarnitine and releaseing CoASH (inhibited by malonyl-CoA so that newly synthesized MCoA is not degraded. Only works in low MCoA conditions) 3. acylcarnitine is transported across in the inner mito membrane by translocase 4. CPTII releases FA-CoA for β-ox, transports carnitine out. - Carnitine deficiency due to diet (often vegans) or genetics (defect in translocase) results in defective β-oxidation |
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β-oxidation
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- cleaves 2C units from straight chain FA's to produce energy. 4 steps:
1. Oxidation - acyl-CoA DH oxidizes α-β bond to double bond with FAD (to FADH2) 2. Hydration - water is add to the double bond 3. Oxidation - C-O bond is oxidized to C=O with NAD+ (to NADH) 4. Cleavage - acyl-CoA transferase cleaves after the β-carbon with CoA [Defect in any of these enzymes would cause accumulation of carnitine-FA and depletion of free carnitine which is pathologic) - 7 cleaves required to break down palmitic acid (get 7 FADH2, 7 NADH, 96 ATP (12ATP/ACoA in the TCA cycle). Total is 131 ATP from palmitic acid |
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Adrenoleukodystrohy (X-Ald)
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- ALD is an X-linked genetic disorder (1:20,000) that leads to demyelination and to primary adrenal insufficiency.
- characterized by the accumulation of (VLCFA), lignoceric (C24:0) and cerotic (C26:0) in brain and in adrenals. - The defect in ALD is in a protein (ABCD1) that transports VLCFA-CoA into peroxisomes for n-oxidation. - Treatment for ALD consists of restricting dietary VLCFA intake and supplementing the diet with Lorenzo’s oil (mixture of olive oil (oleic acid, CI8:1) and rape seed oil (erucic acid, C22:1) and treating with adrenal hormones (cortisol) or stem cells - Since a single ER enzyne complex elongates both saturated and unsaturated fatty acids, Lorenzo’s oil causes a competitive inhibition of the synthesis of saturated VLCFA |
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Ketone bodies
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- acetoacetic acid, β-hydroxybutyric acid
- water soluble, lipid based energy source, formed from acetyl-CoA in the matrix of mitochondria in the liver and kidney (lesser) - becomes the primary fuel source of many tissues when glucose is deficient, especially those that cannot use FA's (brain, also muscle) - upregulation of ketones ensures that glucose is not totally depleted by other tissues during startvation |
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Diabetic Ketoacidosis
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- during glucose starvation there is a depletion of TCA intermediates for gluconeo, and increased FA degradation leading to build up of ACoA, favoring ketone production
- In diabetes there is more glucagon relative to insulin. This results in increased activation of hormone-sensitive lipase (increased TAG cleavage) and inactivation of ACoA carboxylase (decreased MCoA, FA synthesis), therefore CPTI is uninhibited, leading to greater mobilization and β-ox of FAs, accumulating ACoA in heptatic mitchondria, therefore creating ketones. - Both acetoacetic acid and β- hydroxybutyrate are relatively strong acids and lower blood pH causing acidosis. - Ketones are excreted in the urine (ketosis) and can be spontaneously converted to acetone giving the characteristic sweet breath of uncontrolled diabetes |
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Phospholipids
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- polar, ionic lipids composed of 1,2 diacylglycerol and a phosphodiester bridge that links the backbone to some (charged) head group at the 3rd position (usually nitrogenous: choline, serine, enthanolamine, also could be glycerol or myo-inostitol)
- most common in humans are phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine - phospholipases: A, cleaves an acyl group (rich in pancreas secretions, inhibited by glucocorticoids); C, cleaves the phosphate bridge and head (found in liver lysosomes, memrbane version is involved in second messengers); D, cleaves R3 head group (only in plants really) |
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Sphingolipids
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- essential components of all plasma membranes, with highest concentrations in CNS white matter
- almost all common ones are derived from ceramides (FA amide derivatives of sphingosine, usally with a behenic acyl acid, 22:0) in which the fatty acid is attached to sphingosine (carbohydrate). - glangliosides are in the CNS, and have NANA bound - located primarily on the outer leaflet of the plasma membrane - play roles in cellular interactions, growth, and development - Very antigenic (blood group, embryonic, tumor antigens) - genetic disorders in sphingolipid metabolism lead to serious impairment of the CNS and development |
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Cholesterol
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- Cholesterol is the major sterol in humans (not found in plants)
- A ubiquitous and essential component of mammalian cell membranes (present in almost all plasma and intracellular membranes). Most cholesterol in membranes occurs in free, unesterified form. Especially abundant in myelinated structures of brain and central nervous system. Excess is always a problem - Precursor of Bile Salts: Facilitate absorption of TAGs + fat-sol vitamins (act as detergents); excretion of bile acids is the major mechanism for removal of cholesterol (occurs in liver and gall bladder). - Precursor of: steroid hormones (Progesterone, corticosteroids, aldosterone, estrogens, testosterone), vitamins D2 and D3 - non-polar molecule (low solubility) so exists in plasma as cholesterol-esters (70%) or bound to solubilizing lipoproteins (L/H/VLDL) along with TAGs |
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Cholesterol biosynthesis
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- de novo synthesis from actyl-CoA occurs in the cytoplasm or ER of virtually all cells (greatest in liver then intestine, adrenal cortex, and reproductive tissues including ovaries, testis and placenta)
- All carbon atoms are derived from acetate - energy comes from high energy thioester bonds of Acetyl CoA and from ATP - 4 Steps: 1. rate limiting step: acetate to mevalonate (2 acetate → acetoacetyl-CoA → HMG-CoA → mevalonate (via HMG-CoA reductase: competitively inhibited by statin, gene repression). 2. activated isoprene formed (5C unit +2 PO4) (all isoprenoid compounds are derived from this). 3. squalene produce (first cylization). 4 cholesterol is formed by closing bonds in rings on squalene (magic!) |
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Regulation of cholesterol biosynthesis
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- liver plays a major role in regulating cholesterol: 1. expresses majority of LDL receptors (75%, leads to high absorption, reduction of plasma cholesterol, supression of liver cholesterol biosynthesis), 2. is the major site for conversion of cholesterol to bile acids, 3. has the highest levels of HMG-CoA reductase
- synthesis of HMG-CoA reductase and LDL receptor are dependent on the transcription factor, SREBP (binds to short regulatory element (SRE) sequence in the promoter region of several genes to stimulate transcription and expession). SREBP is inhibited by sterols (bind the regulatory protein SCAP) - HMG-CoA reductase is activated by insulin and inhibited by glucagon and intracellular cholesterol. High intracellular cholesterol also activates the conversion to cholesterol-esters (via ACAT) and inhibits LDL-cholesterol receptor mediated endocytosis. - Statins are competitive inhibitors of HMG-CoA reductase because their structure resemble HMG-CoA or mevalonate |
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Excretion of cholesterol
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- Cholesterol cannot be degraded so it is lost through excretion as bile acids (300mg/day), which are synthesized in hepatocytes
- Primary bile acids in humans are cholic acid (helps dissolve lipids for digestion) and chenodeoxycholic acid - Bile acids contains a side chain that ends in a carboxylic acid that is ionized at pH 7.0 (ionized bile acids are called bile salts) - conversion to bile acids is regulated by substrate activation and product inhibition - if bile salt metabolism is defective it can result in gall stones |
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Human disease related to cholesterol
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Hypercholesterolemia
-Plasma cholesterol levels > 200 mg/100 ml -Familial forms result from genetic defects in LDL receptor -Homozygotes often die from heart attacks by age 5 -Heterozygotes (1 in 500 people) develop symptoms of heart disease by age 30. Atherosclerosis (Heart disease and stroke) -Leading cause of death in Western industrialized countries -Disorder of the arterial wall in which cholesterol esters accumulate in macrophages and deposit in the wall to generate a plaque |
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Classes of inborn errors of metabolism (IEM)
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1. Intoxication
- kids tend to be normal at birth because placenta acts as a sink to detoxify blood. Also the become older toxic metabolites accumulate causing phathogenicity - Can usually measure toxic compounds in blood or urine (if water soluble) - can be treated by removal of the toxic compound 2. energetic disorders - complex diagnosis to determine where in the energy process the defect is; require clinical as well as lab assessment(glycogen storage defects are often show up later as babies have small livers and don't store much) - difficult to treat due to lack of accumulation of an enzyme. Complex molecule disorders - lysosomes, perixisomes, CDG (ER/Golgi), cholesterol - is independent of catabolic state and food intake - sometime treated with enzyme replacement therapy |
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Commonly effected pathways that manifest as metabolic disease
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Metabolism of essential amino acids (especially branched chain AAs)
- can result in organic acidemia (all excrete organic acids in urine): maple syrup urine disease, isovaleric acidemia (sweaty feet odor), propionic acidemia, methylmalonic acidemia, but not all errors will result in disease state (the body can excrete toxic metabolites by other pathways) Metabolism of fatty acids - IEMs can result in accumulation of metabolites (inoxication, may be releved by alternate metabolites) or energy deficiency. -Treatment: creatine (to bind metabolites for excretion), small frequent meals/continuous feeds (basically no fasting since no ketones available), high carb, low fat diet |
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Proprionic aciduria
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- defect in propionyl-CoA carboxylase (biotin dependent) resulting in the accumulation of propionyl-CoA .This can then be modified by other substrates, resulting in high blood C3-carnitine , and urine 3-HO-proprionate and methylcitrate
- acute phenotype: life-threatening ketosis/acidosis, hyperammonemia, infection, cardiomyopathy - progressive phenotype: encephalopathy, mental & physical retardation, hypotonia, seizures, lethargy - treatment: Molecular mutation analysis; Diet restricted in Iso, Met, Thr, Val, and odd chain FA's; carnitine supplementation (to bind toxic metabolites for excretion); Biotin supplementation (co-factor, may stabilize protein); Flagyl (kill gut bacteria that produce propionate acid); G-feeds. |
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Goals of therapy for IEMs
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- Provide adequate energy and nutrition
- Maintain positive nitrogen balance - Prevent production of abnormal metabolites: Restriction of offending substrate; Supplementation with downstream metabolites - Remove abnormal metabolites - Supplement cofactors, carnitine, etc as needed |
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Newborn screening
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- began in 1961, not screen up to 40 metabolic diseases by heel stick (20 primary targets, 22 secondary targets)
- not a diagnosis, but indication for further testing |
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Speeds of utilization of different fuel types
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- explains decrease in speed over time: as you switch to slower metabolized energy sources you cannot contract muscle as fast
Fastest to slowest: muscle ATP creatine phosphate (~10 sec to use all this, max/burst velocity) conversion of muscle glycogen to lactate conversion of muscle glycogen to CO2 conversion of liver glycogen to CO2 (not stimulated by muscle contraction (only for brain) so takes longer (hormone stimulation) Conversion of adipose tissue to FAs (also has to transfer resources between tissues, extra slow) |
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Compartmentalization of metabolism
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- Important for separating catabolism and anabolism
-Cytosol: glycolysis, pentose phosphate pathway, FA synthesis, purine synthesis - Mitochondrial matrix: TCA cycle, Oxidative phosphorylation (except VLCFA degradation in peroxisomes), β-oxidation, ketone-body formation - Interplay of both: gluconeogenesis (PyrDH is inside), urea synthesis (until citrulline), pyrimidine synthesis |
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Metabolic activities occurring in a well fed state
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- Glucose is absorbed in the intestine, triggering insulin release from the pancreas which then changes metabolic activity:
↑ glucose uptake in muscle & adipose (by ↑ GLUT4 transporter) ↑ glucose uptake in liver (↑ glucokinase expression) ↑ glyocogen synthesis in liver and muscle (↑glycogen synthase) ↓ glycogen breakdown (↓glycogen phosphorylase) ↑glycolysis, acetyl-CoA production in liver & muscle (↑PFK1 (by ↑PFK2), ↑Pyr DH complex) ↑FA synthesis in liver (↑Acetyl-CoA decarboxylase) ↑TAG synthesis in adipose (and transport from liver as VLDL) (↑Lipoprotein lipase) ↑Protein synthesis & excretion of keto-acids as urea |
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Metabolic activities occurring in a fasted state
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- Low blood glucose (55mg/100mL and below) triggers release of glucagon (and cortisol (increases PEPCK) and EP). This then triggers changes in metabolism:
↑ glycogen breakdown in liver (↑ glycogen phosphorylase) ↓Glycogen synthesis (↓glycogen synthase) ↑gluconeogenesis in liver from AA's (↑protein breakdown, ↑urea cycle), glycerol (FA breakdown), OAA (↓TCA cycle); by (↑FBase-2, ↓pyruvate kinase, ↑PEPCK) ↑fatty acid mobilization in adipose (and then metabolism in liver) (↑hormone sensitive TAG lipase) ↑ketogenesis (Acetyl-CoA carboxylase) |
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Major metabolic pathways liver
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Major Pathways:
Glycolysis, gluconeogenesis, lipogenesis, β-oxidation, citric acid cycle, ketogenesis, lipoprotein metabolism, drug metabolism, synthesis of bile salts, urea, uric acid, cholesterol, plasma proteins Main Substrates: Free fatty acids, glucose (in fed state), lactate, glycerol, fructose, amino acids, alcohol Major Products exported Glucose, triacylglycerol in VLDL, ketone bodies, urea, uric acid, bile salts, cholesterol, plasma proteins Specialist Enzymes Glucokinase, glucose 6-phosphatase, glycerol kinase, phosphoenolpyruvate carboxykinase, fructokinase, arginase, HMG CoA synthase, HMG CoA lyase, alcohol dehydrogenase |
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Major metabolic features of the brain
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Major pathways:
Glycolysis, citric acid cycle, amino acid metabolism, neurotransmitter synthesis Main substrates: Glucose, amino acids, ketone bodies in prolonged starvation Major Products Exported Lactate, end products of neurotransmitter metabolism Specialist Enzymes Those for synthesis and catabolism of neurotransmitters |
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Major metabolic features of the heart
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Major Pathways:
β-Oxidation and citric acid cycle Main Substrates: Ketone bodies, free fatty acids, lactate, chylomicron and VLDL triacylglycerol, some glucose Major Products Exported: none Specialist enzymes: Lipoprotein lipase, very active electron transport chain |
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Major metabolic features of adipose tissue
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Major Pathways:
Lipogenesis, esterification of fatty acids, lipolysis (in fasting) Main Substrates: Glucose, chylomicron and VLDL triacylglycerol Major Products Exported: Free fatty acids, glycerol Specialist enzymes: Lipoprotein lipase, hormone-sensitive lipase, enzymes of pentose phosphate pathway |
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Major metabolic features of skeletal muscle
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Major Pathways:
Fast Twitch (FT): glycolysis; Slow Twitch (ST): oxidative phosphorylation, TCA cycle Main Substrates: FT: glucose, glycogen; ST: Ketone bodies, chylomicron and VLDL triacylglycerol Major Products Exported: FT: Lactate, (alanine and ketoacids in fasting); ST: none (CO2) Specialist enzymes: FT: none; ST: Lipoprotein lipase, very active electron transport chain |
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Major metabolic features of the kidney
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Major Pathways: gluconeogenesis
Main Substrates: Free fatty acids, lactate, glycerol, glucose Major Products Exported: glucose Specialist enzymes: Glycerol kinase, phosphoenolpyruvate carboxykinase |
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Major metabolic functions of the erythrocytes
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Major Pathways: Anaerobic glycolysis, pentose phosphate pathway
Main Substrates: glucose Major products exported: lactate Specialist enzymes: Hemoglobin, enzymes of pentose phosphate pathway |
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Dietary Reference intake value:
Estimated average requirement (EAR) |
= the average daily intake level that meets the requirements for one half of healthy individuals in a life stage or gender group.
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Dietary Reference intake value:
Recommended Dietary Allowance (RDA) |
= the average daily intake level that meets the requirements for most individuals (97-98%). The RDA is not a minimal requirement and actually includes a margin of safety for most individual
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Dietary Reference intake value:
Adequate intake (AI) |
= set when insufficient evidence exists for the calculation of an EAR or RDA. It is based on the nutrient intake levels of healthy people.
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Dietary Reference intake value:
Tolerable Upper Intake Level (UL) |
= the highest average daily intake level for which there is no risk of adverse health effects to most of the population
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Human macronutrient requirements
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- Protein: essential amino acids that the body cannot synthesize, or for use in gluconeogenesis when fats and carbs are inadequate. RDA: 0.8 g/kg body weight (young children should consume 2-3x this, during pregnancy/lactation mothers should consume added 10-15g/day
-Carbohydrates: not "essential" but recommended for caloric use (prevent protein degradation). Complex carbs are best (slower hydrolysis). RDA = 130g/day (can be exceeded for higher energy needs), ~45-65% of calories/day. Fiber AI = 25g/day (women) 38g/day (men) - Dietary Fats: essential FA's: linolinic acid (omega-3) & linoleic acid (omega-6) (both important for phospholipid synthesis). RDA's not established for ω3/6, recommended 2-4g ω6, 0.2-0.4g ω3. Total fat ~20-35% of calorie intake |
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Micronutrients and their importance in diet
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= compounds required in small amounts in the diet because they are required for enzyme function (co-factors, structural elements, signaling molecules). Includes vitamins an minerals
- vitamins are essential organic compounds obtained by diet. Either water soluble (mostly co-enzymes) or fat soluble (prone to toxicity b/c not excreted by kidney) - Minerals: inorganic compounds, usually only require micro-milligrams per day (except calcium, phosphorus, and magnesium) |
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Thiamine (B1) function and deficiencies
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-Water soluble
Function: In the form of thiamine pyrophosphate, it is a cofactor for: 1. Pyruvate dehydrogenase (glycolysis); 2. Alpha ketoglutarate dehydrogenase (TCA cycle); 3. Pentose P Pathway; 4. Branched-chain AA dehydrogenase Deficiency: -Beriberi (severe lethargy + fatigue, complications with cardiovascular, muscular, nervous, GI systems), polyneuritis, Wernicke-Korsakoff syndrome, loss of memory, eye movements |
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Riboflavin (B2) function and deficiencies
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-Water soluble
FUNCTION: cofactor in redox reactions (FADH2) DEFICIENCY: cheilosis (inflammation of lips), angular stomatitis (scaling/sores at corners of mouth), dermatitis |
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Niacin (B3) function and deficiency
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-Water soluble
FUNCTION: used to make NAD+/NADP+ which is a coenzyme/cosubstrate for hydrogen transfer with many dehydrogenases DEFICIENCY: Pellagra = characterized by dermatitis, diarrhea, dementia (and death) |
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Vitamin B6 function and deficiency
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- Water soluble
FUNCTION: comes in 3 forms, pyridoxine, pyridoxamine, pyridoxal; active form is pyridoxal phosphate which is: 1. cofactor for transamination (alanine transaminase, aspartate aminotransferase) = metabolism of amino acids 2. Cofactor for neurotransmitter biosynthesis; used in decarboxylating AA’s to make neurotransmitters 3. Glycogen metabolism 4. Sphingoid base metabolism DEFICIENCY: nasolateral seborrhea (dermatitis next to nose), glossitis (tongue swollen/changes color), neuropathy |
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Biotin, function and deficiency
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-Water soluble
FUNCTION: cofactor for carboxylation enzymes: 1. Pyruvate carboxylase, in gluconeogenesis 2. Acetyl CoA carboxylase, committed step in fatty acid synthesis 3. Propionyl-CoA carboxylase DEFICIENCY: fatigue, depression, nausea, dermatitis, muscular pain |
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Pantothenic Acid (B5) function and deficiency
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- Water soluble
FUNCTION: 1. Essential part of coenzyme A, which is necessary for acyl transfers 2. Essential part of fatty acid synthase DEFICIENCY: fatigue, sleep disturbances, impaired coordination, nausea |
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Folic acid function and deficiency
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-Water soluble
FUNCTION: Converted to tetrahydrofolate (THF), which is a coenzyme that functions in single-carbon transfers in metabolism of nucleic and amino acids. Needed for conversion of homocysteine to methionine by homocysteine methyltransferase DEFICIENCY: megaloblastic anemia, birth defects (neural tube defects). To avoid birth defects, need folate supplementation ABOVE normal dietary intake; need it during first 3 weeks of pregnancy |
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Vitamin B-12 function and deficiency
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-Water soluble
FUNCTION: Coenzyme functions in metabolism of odd number fatty acids and methyl transfers. Also is a cofactor for homocysteine methyltransferase and methylmalonyl CoA mutase DEFICIENCY: pernicious anemia, neurological disorders, dementia |
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Vitamin C (ascorbic acid, dehydroascorbic acid) function and deficiency
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-Water soluble
FUNCTION: Formation of collagen, carnitine; important as antioxidant DEFICIENCY: scurvy with petechiae, spongy + bleeding gums, poor wound healing |
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Differing qualities of macronutrients/macronutrient rich foods
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Protein:
- animal protein is higher quality than vegetable because it has a good balance of essential amino acids. For vegetarians protein balance is often a bigger issue than total intake. Carbohydrates: - complex sugars are preferable to simple because they have a lower gylcemic index (help increase satiety, decrease total intake). Fiber is important for maintaining colonic/flora health, motility, decreased fatty absorption, and lowered postprandial glucose levels. Fats: Saturated fats area associated with high plasma cholesterol and increased risk of CHD, trans fats decrease membrane fluidity and have same risks. Mono-unsaturated FA's are best. |
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Vitamin A (retinol, retinal) solubility, function, deficiency, excess
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- Fats soluble
FUNCTION: part of visual pigment molecules; involved in cellular differentiation and proliferation DEFICIENCY: night blindness, xerophthalmia (dryness in the eyes), keratomalacia (dry cornea) EXCESS: birth defects, vomiting, diplopia (double-vision), alopecia (hair loss), desquamation (skin coming off), bone abnormalities |
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Vitamin D (cholecalciferol in milk/sun-exposed skin, ergocalciferol ingested from plants) solubility, function, deficiency, excess
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- fat soluble
FUNCTION: increases intestinal absorption of calcium and phosphate, mineralization of bones and teeth DEFICIENCY: rickets (children) and osteomalacia (adults) in which bones are softened/weakened; colon/breast cancer risk EXCESS: nausea, vomiting, anorexia, diarrhea, loss of weight; *calcification of soft tissue especially kidney + heart |
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Vitamin E (tocopherols, tocotrienols) solubility, function, deficiency, excess
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- Fat soluble
FUNCTION: antioxidant for cell membrane, unsaturated lipids, and low density lipoprotein DEFICIENCY: increased fragility of erythrocytes resulting in hemolytic anemia, muscle weakness/degeneration, nerve degeneration EXCESS: relatively nontoxic, but may antagonize vitamin K in those on anticoagulant therapy |
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Vitamin K (phylloquinones, menaquinones) solubility, function, deficiency, excess
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FUNCTION: formation of blood clotting proteins that bind calcium
DEFICIENCY: hemorrhagic disease EXCESS: relatively nontoxic |
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Principles of the prudent diet
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- Adequate nutrients within energy needs: nutrient dense, not energy dense foods
- Fat intake: 20-35% of calories, mostly poly/monounsaturated, <10% cals saturated fat, <300mg/day cholesterol, >0.8g/d omega-3, avoid trans fats - Fruits and vegetables: 9+ servings/day, varied among colors, 2 c/d fruit and 2.5 c/d veg - Protein: maintain at moderate levels and focus on lean meats and plant proteins - Whole grain foods: which have fiber and nutrients and allow for better glucose control (lower glycemic index) - Alcohol: never during pregnancy, only if adequate high nutrient density foods are consumed, never counsel to begin drinking due to risk of addiction - Salt intake: limit intake to 6g NaCl/2300mg sodium or less, increase foods rich in potassium - Calcium: maintain adequate calcium intake (1.0-1.2g/day) - Supplements: needed for women of childbearing years (iron, folate), the elderly (vit B12), people who do not get much sunlight (vit D) - Fluoride: needed to reduce risk of dental cavities |
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Emerging concepts in food selection and functional foods
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Functional foods: food beyond nutritional requirements that are beneficial to health. It is thought that many functional food components have anti-inflammatory and/or anti-oxidant effects, which lead to overall health by reducing
cell damage. EX: - phytochemicals carotenoids (antioxidants), flavonoids (protective enzymes), and glutathione synthesis - fiber: controls blood glucose, improves gut motility, binds toxic substances, and decreases risk of colon cancer Food selection: food pyramid has been replaced by myplate template, which reflect current understanding of a healthy diet: fruits, vegetables, whole grains, lean protein. Intended to be more intuitive. |
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Studies on impact of diet on disease prevalence
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- Seven countries study: mid 20th C., showed correlations between cardiovascular disease incidence & mortality and serum cholesterol & dietary fat content in middle age men over 15yrs. Indicated positive association between CHD and sat. fat and negative with mono-unsat. fat; unrelated to protein, carb, alcohol intake. Greek/Medit & Japanese diets ~ lower mortality than US/Finland (higher animal fat)
-Lyon Heart study: 605 patients randomized to prudent or mediterranean diet over 4yrs. Mediterranean showed higher compliance, 56% reduction in mortality, 61% reduction in mortality - Framingham heart study (1948-ongoing): 5,000 people longitudinally. Helped develop strategies of cardio disease prevention. Showed importance of healthy diet, weight management, regular exercise in good health. Confirmed smoking is risk for CHD (leading to angina, MI, death) |
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Resveratrol
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=a polyphenol/ anti-oxidant found in red wine.
- It has been found to improve the health and survival of mice on high calorie diet. - How it works: SIRT1, identified as a longevity gene in worms, migrates to break sites in DNA to repair DNA and has other powerful metabolic effects. It deacetylates and activates PGC-1a, a molecule with a broad portfolio of activities. PGC-1a is a coactivator (doesn’t bind to DNA itself) that binds to NRF-1 so that mitochondrial and oxidative phosphorylation-promoting genes can be expressed. GCN5 is an acetylase that acetylates PGC-1a so that it inactivates. Exercise and resveratrol have been found to deacetylate the molecule, leading to transcription. |
