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246 Cards in this Set
- Front
- Back
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Alternate Names for Pentose Phosphate Pathway
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-Hexose Monophosphate Shunt
-6-Phosphoroglucontate pathway |
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Pentose Phosphate Pathway Products
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NADPH for reductive biosynthesis
-fatty acids and steroids Ribose-5-phosphate -Nucleic Acids Glycolytic Intermediates -glyceraldehyde-3-phosphate -Fructose-6-phosphate |
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Adenine nucleotides and energy charge reciprocally regulate
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catabolic and anabolic pathways
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PPP:
Glycolysis to |
Pyruvate Dehydrogenase to
Tricarboxylic Acid Cycle |
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Negative and Positive for Glycolysis, Pyruvate Dehydrogenase, and Tricarboxylic Acid Cycle in PPP
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Negative: NADH, ATP
Positive: NAD+ |
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Oxidative Phosphorylation in PPP
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ADP to ATP
NADH to NAD+ |
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In PPP:
Higher requirement for NADPH than |
ribose-5-phosphate- complete oxidation of G6P to CO2 and resynthesis of G6P and ribulose-5-P.
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In PPP:
Higher requirement for ribose-5-P than |
NADPH, G6P is converted to fructose-6-P and glyceraldehyde-3-P by glycolytic pathway
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Cycle:
PPP to |
NADPH (Coemzyme for reductive biosynthesis)
to Sugar Interconversions (ribose-5-P for nucleotides) |
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PPP Stage I
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Generates 2 pairs of e-
Start: Glucose-6-P (G6P) End: Ribulose-5-P Decarboxylation of hexose to pentose yielding NADPH. IRREVERSIBLE |
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PPP Stage II
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Start and end with 5C
Interconversions of pentose-Ps leads to glycolytic Intermediates(REVERSIBLE) |
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Glucose-6-Phosphate Dehydrogenase
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Catalyzes the first step in the pentose phosphate pathway
Rate limiting step- Glucose-6-phosphate to 6-phospho-gluconate Uses NADP as a cofactor (reaction generates NADPH) Highly regulated by NADPH/NADP ratio |
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NADPH/NADP Ratios
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Cellular Feedback Mechanism
NADPH/NADP = high = inhibits G6PD NADPH/NADP = low = activates G6PD |
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NADPH
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Primarily uses high energy electrons for biosynthesis
Fatty Acids Steroids |
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NADH
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(Reduced Form)
Uses high energy electrons to make energy (ATP via oxidative phosphorylation) |
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Functions of NADPH
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Provide high energy electrons for reductive
biosynthesis Used as a cofactor by enzymes that deal with reactive oxygen species (ROS) NADPH has a uniqure role in biosynthesis b/c the pthwy & direction of glucose-6-phosphate is determined by the needs of the cell for NADPH or sugar intermediates These functions cannot be replaced by NADH |
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ROS
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Reactive Oxygen Species - Bad Species
Highly reactive O2 and H2O2 Can break strands of DNA & when ody repairs, can cause mutations |
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ROS and DNA
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genetic mutation
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ROS and Lipids
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membrane function
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ROS and Protein
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enzyme inactivation
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O2-
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Superoxide Anion-produced biologically by
a variety of reactions most notably by “leaky” mitochondrial electron transfer. Electrons can be Transferred from the reduced form of Coenzyme Q to oxygen, thus generating superoxide |
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H2O2
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Hydrogen Peroxide: produced by oxidase enzymes. Very toxic organic peroxides can be formed from 2e- reduction of O2 in compounds containing double bonds (unsaturated fatty acids).
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OH-
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Hydroxyl Radical: produced from a metal catalyzed reaction of superoxide and hydrogen peroxide. Very reactive species that can take part
in free radical chain reactions. |
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Glutathione
What is it and function |
A Multifunctional Peptide
Function: Major cellular reductant and suflhydryl buffer, conjugated to drugs to make them more soluble, amino acid transport across membranes, disulfide interchanges in proteins. |
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Cellular Defense Against Oxidative Stress
1 |
Superoxide Dismutase (SOD)-detoxifies superoxide
2H+ + 2O2- H2O2 + 2 O2 MnSOD (mitochondrial enzyme) Cu-ZnSOD (cytoplasmic enzyme)- enzyme deficiency leads to Severe progressive neurodegenerative disorder: Lateral Sclerosis (ALS) or Lou Gherig’s Disease |
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Cellular Defense Against Oxidative Stress
2 |
Catalase-heme containing peroxidase that detoxified H2O2
2H2O2 2H2O + O2 |
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Cellular Defense Against Oxidative Stress
3 |
There are no known enzymatic systems that deal directly
With hydroxyl radicals. Cells rely on the above two reactions To remove precursors to ROS> |
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Cytochrome P-450 System
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Liver enzymes detoxify many nasty compounds:
-Drugs -Steroids -Alcohols These enzymes require NADPH as a cofactor. |
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Clinical Correlation: Glucose-6-P Dehydrogenase (G6PD) Deficiency
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Lack of G6PD results in loss of NADPH production, loss of Glutathione antioxidant system, increased oxidative stress,
Membrane damage and red blood cell lysis. X-linked disease is the most common disease causing enzymatic defect in humans (200 million people world wide). Hemolytic anemia caused by this mechanism can be precipitated by oxidant drugs (e.g., primaquine), diet (fava beans), infection (induction of NADPH Oxidase). |
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G6PD Mutations
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Slightly decreased life span (complications from hemolysis).
Many mutations alter G6PD function. Many alter the Km and Vmax of the enzyme Some mutations confer resistance to flaciparum malaria 3 major drug markets: US, Europe, Asia |
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Drugs that Exacerbate G6PD
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Antibiotics
e.g., sulfamethoxazole Antimalarials e.g. primaquine, chloroquine Antipyretics e.g. acetanilide (should not be used) NOT aspirin or acetaminophen |
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Pentose Phosphate Pathway Summary
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Pentose Phosphate Pathway
-NADPH, Ribose-5-phosphate, other 3-7 carbon carbohydrate interconversions. Role of NADPH -Reductive Biosynthesis -Required for enzymes (glutathione reductase) that deal with reactive O2 species. Mutations in the rate-limiting enzyme G6PD |
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Glucuronic Acid
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Importance: Glucuronic acid is conjugated to endogenous and exogenous compounds producing a strongly acidic compound that is more water soluble at physiological pH than its precursor.
Important in (LIVER): Drug detoxification Steroid excretion Bilirubin metabolism |
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Glucuronic Acid Synthesis
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Start: glucose
End: D-Glucuronic acid Many intermediates |
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Lipid: location and function
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Hydrophobic
Most contain or derived from fatty acids Many functions: a) major fuel store b)constitute membranes c) solubalize nonpolar substance in bodily fluids (bile acids) d) important signaling molecules (scosiniods/prostaglandins) |
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Fatty Acid Structure
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Alkyl chain with a terminal carboxyl group R-COOH
Saturated CH3(CH2)nCOOH Unsaturated (up to 6 double bonds) bent shape Most akyl chains have an even number fo carbon atoms usually 12-24 |
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Numerical Formulas
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Show number of carbon atoms, number of double bonds, and bond location starting with carboxyl carbon.
Nervonic acid 24:1(15) Count from Omega end |
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Triacylglycerols (TAGs)
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Three fatty acids esterified to a glycerol backbone
On a weight basis, pure TAG yields 2.5 times more ATP than pure glycogen TAGs can be stored without associated water, thus decreasing the storage weight. |
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Digestion and Absorption of Lipids
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Adults ingest 60-150 gm of lipid/day. Triacylglycerols constitute 90% of dietary fat.
Other 10% are phospholipids, cholesterol, cholesterol esters, and free fatty acids. |
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Density
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From least to most:
Chylomicron, VLDL, IDL, LDL, HDL |
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Lipoproteins in Liver & Intestine
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generate HDL
Lowest TAG, high cholesterol Deliver cholesterol to liver for elimination |
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Lipoproteins in VLDL (very low density lipids)
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generates
Low TAG, Highest cholesterol Deliver cholesterol to peripheral tissues and liver |
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Lipoproteins in Liver
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generates VLDL
High TAG, low cholesterol deliver de novo TAG to peripheral tissues |
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Lipoproteins in Intestine
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generates Chylomicron
Highest TAG, lowest cholesterol Deliver dietary TAG to peripheral tissues |
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Lipid Transport in Fed State
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Liver TAGs :
FA synthesized from excess carbohydrate and amino acids FA assembled into TAGs, packaged into VLDL, secreted into the blood stream (chylomicrons to cytoplasm) VLDL and chylomicrons are hydrolyzed by lipoprotein lipase (endothelial cells in muscle and adipose tissue) ApoC-II (apoprotein lipase) activates binding products (FA & glycerol) taken up reassembled to TAG (adipose), or used as fuel (muscle) |
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Mechanisms if fed state vs fasted state
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more feedback mechanisms in the fasted state
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Lipid Transport in Fasted State
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TAGs in adipose mobilized
Hormone-sensitive lipase activated by phosphorylation by cAMP-dependent protein kinase A Perilipin not phosphorylated blocks lipase access to TAG (hormome sensitive) Once hydrolysis complete, FAs and glycerol released into the blood. FAs transported by serum albumin PROLONGED fasting liver makes ketone bodies, acetoacetate and b-hydroxybutyrate |
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Fatty Acid Biosynthesis
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Occurs in the cytosol
Palmitic acid (C16H32O2) is first synthesized from carbohydrate intermediates, amino acids and other fatty acids. All other fatty acids are made by modification of palmitic acid. Acetyl CoA provides all the carbons for FA synthesis in two carbon units. Sequence of reactions is carried out by fatty acid synthase. |
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Transfer of Acety CoA from mitochondria to cytosol for fatty acid biosynthesis by the citrate cleavage pathway
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Occurs in mitochondria
Pyruvate can't cross. Must be converted to citrate Citrate Synthase is the 1st citric acid cycle step |
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Acetyl-CoA carboxylase
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Biotin is a coenzyme
-Requires 1 molecule of ATP and HCO3 -Biotin is a coenzyme that transfers the CO2 to Acetyl-CoA to yield malonyl-CoA -Key control point for fatty acid synthesis -Citrate is an allosteric activator -Palmitoyl CoA is an allosteric inhibitor -Glucagon and cAMP promote inactivation by AMP-mediated phosphorylation -Dephosphorylation activates Acetyl-CoA Carboxylase -Diet controls pathway by regulating enzyme synthesis |
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Mammilian Fatty Acid Synthase
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Multienzyme polypeptide that is composed of 2 identical subunits
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How do we release palmetic acid?
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Palmitoyl-ACP acted on by thioesterase to produce palmitic acid
Both sulfhydryl groups of synthase and ACP are free, so another round of FA synthesis can begin |
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Characteristics of Fatty Acyl Synthase
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It is essential, but not rate limiting
Not subject to short term control All activities on a single contiguous protein In animals, the synthase is active only as a dimer |
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Palmitate Modifications for Formation of Other Fatty Acids
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-Elongation of Fatty Acids
Occurs in the endoplasmic reticulum (from maloyl CoA) or mitochondria (from Acetyl CoA) -Desaturation of Fatty Acids Occurs in endoplasmic reticulum (enzyme is monoxygenase) -Hydroxylation of Fatty Acids Occurs in mitochondria of many tissues Occurs in tissues of the nervous system where long chain fatty acids are needed (C22 and C24) |
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Pathway of fatty acid elongation in mitochondria
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Preferred substrate is palmitoyl CoA
Intermediates are acetyl-CoA esters Converts palmitate to stearate for tissues except the brain. Chains are extended up to C24 NADH and NADPH serve as reducing agents |
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Desaturation of Fatty Acids
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Requires the combination of desaturase enzyme,
cytochrome b5 and NADPH-cytochrome b5 reductase. Occurs at C 4,5,6,9 Unsat fatty acids essential to humans US has a lower MP and liguid at RT Fatty acids usually stored as triglycerides |
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Storage of fatty acids as triacylglycerols
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Structure of TAG
Synthesis of glycerol phosphate Free fatty acid is converted to activated form (usually attached to Acetyl CoA) Triacylglycerols are synthesized from Fatty Acyl CoAs and Glycerol 3-Phosphate |
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Synthesis of Triacylglycerols
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Formed by activated fatty
acids and products of glucose metabolism. The first step is formation of phosphatidic acid. |
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Synthesis of Triacylglycerols cont
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Fed State: Glycolysis
Fasted State: Pyruvate Backbone of TAG: glycerol-3-phosphate 1st step: lysophosphatidic acids |
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Synthesis of Triacylglycerols cont
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Activated form of fatty acid: fatty acyl CoA pool
Complex Lipids: Sphingomyleins and glycerol phosphlipids Synthesized: Triacylglycerols |
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Carnitine Transport of Acyl Groups Across the Inner Mitochondrial Membrane
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Fatty acyl CoAs are formed outside mitochondria.
Oxidizing enzymes are located in the inner mitochondrial membrane Membrane is impermeable to CoA Carnitine is the transport molecule for fatty acids into the mitochondrial matrix. Oxidation of FA occurs here. |
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Carnitine Mediated Transport of Fatty Acids into Mitochondria for Oxidation
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1.) Fatty acid transferred to carnitine by carnitine-palmitoyl transferase (CPTI) to yield acylcarnitine.
2.) Acylcarnitine is translocated across the inner mitochondrial membrane by translocase. 3.) Fatty acid is transferred to CoASH by CPTII and carnitine is recycle back to the intermembrane space to react with another fatty acid. |
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Fatty Acid b-Oxidation
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FAS are oxidized sequentially 2 carbons at
a time. Sequential steps are: Dehydrogenation Hydration Oxidation Oxidized while attached as a thioester to 4-phosphopantetheine of CoA. Each set of oxidations produces: -1 acetyl-CoA-10 ATPS -1 FADH2- 1.5 ATPs -1 NADH- 2.5 ATPs |
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Overall yield of Fatty Acid b-Oxidation
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Oxidation of palmitate yields 7 oxidations
with 1 acetyl CoA as the final product. The Overall yield is (7X14ATPS) + 10 ATPS- (2ATPS for palmitate to palmitate-CoA)= 106 ATPS. |
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Additional Enzymes
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b-oxidation oxidizes saturated fatty acids with even number
Odd-chains produce propinolyl CoA Unsaturated fatty acids require additional enzymes a- oxidation is necessary for metabolism of branched chain fatty acid, uses fatty acid a hydroxylase (Refsum disease) occurs in peroxisomes - Rare b/c not in mitochindria |
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synthesis
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Subcellular location: Cytosol
Carriers of acyl/acetyl groups: Citrate Acyl carrier: Acyl Carrier protein Activator: Citrate Inhibitor: long-chain fatty acyl CoA Product of pathway: Palmitate Repetitive four-step process: Condensation, reduction, dehydration, reduction |
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degradation
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Subcellular location: Mitochondria
Carriers of acyl/acetyl groups: Carnite Acyl carrier: CoA Activator:? Inhibitor: Malonyl CoA Product of pathway: Acetyl CoA Repetitive four-step process: Dehydrogenation, hydration, dehydration, thiolsis |
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Ketone Bodies: an alternate fuel for cells
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Water soluble lipid based energy: acetoacetic acid and b-hyrdroxybutyric acid.
Primary site of formation is the liver. Process occurs in the mitochondrial matrix. b-hydroxy-b-methylglutaryl CoA (HMG-CoA) is intermediate in acetoacetate synthesis from acetyl-CoA. |
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Ketone Body Synthesis
Key Enzymes |
HMG CoA Synthase & HMG CoA Lyase. Located in liver
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Ketone Body Synthesis
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2 acetyl-CoA molecules are condensed
to form acetoacetyl-CoA by b-ketothiolase. Acetoacetyl-CoA is condensed with a second acetyl-CoA to form HMG-CoA by HMG-CoA synthase. HMG-CoA is cleaved by HMG-CoA lyase to yield acetoacetic acid plus acetyl-CoA. Acetoacetic acid is reduced to d-b-hydroxy- butyrate by b-hyrdoxybutyrate dehydrogenase to yield hydroxybutyrate at the expense of 1 NADH. Acetoacetic acid spontaneously forms acetone + CO2. Absence of HMG-CoA lyase results in HMG-CoA being used for cholesterol synthesis. |
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Ketone Bodies
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Ketone body formation can be considered an overflow pathway.
Stimulated when acetyl-CoA accumulates due to deficient carbohydrate utilization, oxaloacetate levels are low, citrate synthase activity is low and accumulation of acetyl-CoA results. Energy is derived from beta-hyrdoxybutyrate being converted to acetoacetyl-CoA in tissues other than the liver, such as the heart and muscle. This conserves carbohydrate for metabolism by the brain. |
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Ketone Bodies Flow Chart
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B-hydroxybutyrate to acetoacetate (NAD+ to NADH + H+)
acetoacetate to Acetoacetyl-CoA (Succinyl-CoA to Succinate) Acetoacetate: succinyl CoA Transferase - not in liver but in peripheral tissue |
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Diabetic Ketoacidosis
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The absence of insulin, the primary anabolic hormone, means that tissues such as muscle, fat, and liver do not take up glucose.
Counter regulatory hormones, such as glucagon, growth hormone, and catecholamines, enhance triglyceride breakdown into free fatty acids and gluconeogenesis, which is the main cause for the elevation in serum glucose in DKA. Beta-oxidation of these free fatty acids leads to increased formation of ketone bodies. |
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Diabetic Ketoacidosis (cont)
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Overall, metabolism in DKA shifts from the normal fed state characterized by carbohydrate metabolism to a fasting state characterized by fat metabolism.
Secondary consequences of the primary metabolic derearrangements in DKA include an ensuing metabolic acidosis as the ketone bodies produced by beta-oxidation of free fatty acids deplete extracellular and cellular acid buffers. |
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Diabetic Ketoacidosis (cont)
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The hyperglycemia-induced osmotic diuresis depletes sodium, potassium, phosphates, and water as well as ketones and glucose.
Commonly, the total body water deficit is 10%, and the potassium deficit is 5 mEq per kg of body weight. The total body potassium deficit may be masked by the acidosis, which sustains an increased serum potassium level. The potassium level can drop precipitously once rehydration and insulin treatment start. |
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Regulation of Lipid Metabolism - Synthesis
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Increase release of insulin
Increase protein phosphatase activity + Acetyl CoA carboxylase Malonyl CoA |
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Regulation of Lipid Metabolism - Degredation
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Increase release in glucagon, epinepherine
Increase protein kinase activity + hormone sensitive lipase |
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Most abundant phospholipid in humans
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Phosphatidlcholine (lecthin)
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Which phospholipids are an ether and not esters?
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ethanolamine plasmalogen and platlet activating factor
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Phospholipid Surfactant
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Dipalmitoylphosphatidylcholine (DPCC) (dipalmitoyllecithin) (16:0) is the major component of surfactant in the lungs (80%).
It is produced by type II epithelial cells and prevents atelectasis. Decreases surface tension of the fluid layer of the lung. Surfactant also contains: PG, PI and 2 surfactant proteins. |
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Phosphatidic Acid Synthesis
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2 sequences to synthesize
start with glycerol 3-phosphate end with diacyglycerol |
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Phosphatidylcholine Synthesis
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Start with choline from diet.
Rate limiting step is the cytidylyl transferase reaction. Binding of cytosolic inactive enzyme, activates it. Regulated by cAMP and fatty acyl-CoA. cAMP dependent protein kinase phosphorylation dissociates enzyme from ER membrane and makes it inactive. Dephosphorylation and rebinding activates enzyme |
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Phosphatidylethanolamine Synthesis
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Start with Ethanolamine Phosphotransferase from liver or brain.
Repeated methylation involved |
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Phospholipid Remodeling: Asymmetric Phospholipids
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Begin with phospholipids.
Glucocorticoids inhibit. Phospholipase A1 to 2-Acyl-lysophosphatide Phospholipase A2 to 1-Acyl-lysophosphatide Phospholipase A1 and A2 can remove fatty acids selectively from either carbon 1 or carbon 2 of the glycerol backbone. |
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Roles of Cholesterol
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Membrane structure
A precursor for the synthesis of the steroid hormones and bile acids. Both dietary cholesterol and that synthesized de novo are transported through the circulation in lipoprotein particles. The same is true of cholesteryl esters, the form in which cholesterol is stored in cells. |
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Regulation of Cholesterol Synthesis
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The synthesis and utilization of cholesterol must be tightly regulated in
order to prevent over-accumulation and abnormal deposition within the body. Of particular importance clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the coronary arteries. Such deposition, eventually leading to Atherosclerosis, is the leading contributory factor in diseases of the coronary arteries. |
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Most plasma cholesterol is?
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Most plasma cholesterol is in an esterified form, with a fatty acid attached at C-3. This makes it even more hydrophobic then free cholesterol.
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Cholesterol Biosynthesis
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All carbon atoms of cholesterol are derived from acetate.
Reducing power in the form of NADPH is provided mainly by glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase of the pentose phosphate pathway The first two reactions in cholesterol biosynthesis are shared by the pathway that produces ketone bodies |
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RLS of Cholesterol Biosynthesis
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HMG-CoA Reductase
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5 Steps of Cholesterol Biosynthesis
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1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA
(HMG-CoA) 2. HMG-CoA is converted to mevalonate 3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO2 4. IPP is converted to squalene 5. Squalene is converted to cholesterol. |
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Cholesterol Biosynthesis Features
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The acetyl-CoA utilized for cholesterol biosynthesis is derived from an
oxidation reaction (fatty acids or ketogenic amino acids) in the mitochondria and is transported to the cytoplasm by the same process for fatty acid synthesis. All the reduction reactions of cholesterol biosynthesis use NADPH as a cofactor. Acetyl-CoA units are converted to mevalonate by a series of reactions that begins with the formation of HMG-CoA. HMG-CoA is converted to mevalonate by HMG-CoA reductase. HMG-CoA reductase absolutely requires NADPH as a cofactor and two moles of NADPH are consumed during the conversion of HMG-CoA to mevalonate. |
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Critical Point of Cholesterol Biosynthesis
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The reaction catalyzed by HMG-CoA reductase is the rate limiting step of cholesterol biosynthesis, and this enzyme is subject to complex regulatory controls
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Regulation of HMG CoA Reductase
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HMG CoA inactive to active
HMG-CoA reductase is most active in the dephosphorylated state. Phosphorylation is catalyzed by AMP-activated protein kinase, AMPK Insulin stimulates the removal of phosphates and, thereby, activates HMG-CoA reductase activity. - IN LIVER |
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Drug Therapy for Dyslipidemia
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Statins-competitive inhibitors of HMG-CoA Reductase.
5 large well controlled clinical trails have documented safety and efficacy for: Simvastatin Pravastatin Lovastatin Reduces fatal and non-fatal coronary heart disease (CHD), strokes and total mortality. |
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Drug Therapy for Dyslipidemia (cont)
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Statins exert their major effect-reduction of LDL levels-through a mevalonic acid-like moiety that competitively inhibits HMG-CoA reductase by product inhibition.
Statins affect blood cholesterol levels by inhibiting cholesterogenesis in the liver, which results in increased expression of the LDL receptor gene. The greater number of LDL receptors on the surface of hepatocytes results in increased removal of LDL from the blood thereby lowering LDL-C levels. |
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Excess LDL leads to cholesterol deposited on
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Cell wall
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The Utilization of Cholesterol
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Cholesterol is transported in the plasma predominantly as cholesteryl esters associated with lipoproteins.
Dietary cholesterol is transported from the small intestine to the liver within chylomicrons. Cholesterol synthesized by the liver, as well as any dietary cholesterol in the liver that exceeds hepatic needs, is transported in the serum within LDLs. The liver synthesizes VLDLs and these are converted to LDLs through the action of endothelial cell-associated lipoprotein lipase. |
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The Utilization of Cholesterol (cont)
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Cholesterol found in plasma membranes can be extracted by HDLs and esterified by the HDL-associated enzyme LCAT.
The cholesterol acquired from peripheral tissues by HDLs can then be transferred to VLDLs and LDLs via the action of cholesteryl ester transfer protein (apo-D) which is associated with HDLs. Reverse cholesterol transport allows peripheral cholesterol to be returned to the liver in HDLs. Ultimately, cholesterol is excreted in the bile as free cholesterol or as bile salts following conversion to bile acids in the liver. |
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Bile Acids - general
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The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%).
These are referred to as the primary bile acids. Within the intestines the primary bile acids are acted upon by bacteria and converted to the secondary bile acids, identified as deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). In liver the carboxyl group of primary and secondary bile acids is conjugated via an amide bond to either glycine or taurine before their being resecreted into the bile canaliculi. These conjugation reactions yield glycoconjugates and tauroconjugates, respectively. |
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Clinical Significance of Bile Acid Synthesis - 4 physiologically significant functions
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1. their synthesis and subsequent excretion in the feces represent the only significant mechanism for the elimination of excess cholesterol.
2. bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing the precipitation of cholesterol in the gallbladder. 3. they facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases. 4. they facilitate the intestinal absorption of fat-soluble vitamins. |
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Sphingolipids - General
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Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath.
Sphingomyelins are sphingolipids that are also phospholipids. Sphingomyelins are important structural lipid components of nerve cell membranes. The predominant sphingomyelins contain palmitic or stearic acid N-acylated at carbon 2 of sphingosine. |
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Ptotective Sphingolipid Structural Features
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The sphingolipids, like the phospholipids, are composed of a polar head group and two nonpolar tails.
The core of sphingolipids is the long-chain amino alcohol, sphingosine. Amino acylation, with a long chain fatty acid, at carbon 2 of sphingosine yields a ceramide. |
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Sphingomyelin Synthesis
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Sphingolipids include the sphingomyelins and glycosphingolipids
(the cerebrosides, sulfatides, globosides and gangliosides). Sphingomyelins are sphingolipids that are also phospholipids. The sphingomyelins are synthesized by the transfer of phosphorylcholine from phosphatidylcholine to a ceramide in a reaction catalyzed by sphingomyelin synthase. |
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Endproducts of Sphingomyelin Synthesis
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Sphingomyelin and Diacylglycerol
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Degredation of Sphingomyelin
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Sphingomyelin is degraded by sphingomyelinase, a lysosomal enzyme
that hydrolytically removes phosphorylcholine, leaving a ceramide. |
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Sphingomyelin Degredation Diseases
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All are rare storage diseases
Gaucher's Disease - easiest to treat with ceramide enzyme Krabbe Disease Niemann-Pick Disease |
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Disease States Resulting from Defective Spingomyelinase
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Defects in the enzyme acid sphingomyelinase result in the lysosomal storage disease known as Niemann-Pick disease.
In Niemann-Pick disease, lipid, mainly sphingomyelin, accumulates in reticuloendothelial and other cell types throughout the body. The accumulation in ganglion cells of the central nervous system leads to cell death. |
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Disease States Resulting from Defective Spingomyelinase
(cont) |
Hepatosplenomegaly, retarded physical and mental growth
and severe neurologic disturbances are features. Symptoms usually develop by 6 months and death occurs by 3 years of age. There are at least 4 related disorders identified as Niemann-Pick disease Type A and B (both of which result from defects in acid sphingomyelinase), Type C1 and a related C2 and Type D. Types C1, C2 and D do not result from defects in acid sphingomyelinase |
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Glycosphingolipids
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Have ceramide backbones
Glycosphingolipids, or glycolipids, are composed of a ceramide backbone with a wide variety of carbohydrate groups (mono- or oligosaccharides) attached to carbon 1 of sphingosine. The four principal classes of glycosphingolipids are the cerebrosides, sulfatides, globosides and gangliosides. |
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Glycosphingolipids
(cont) |
Cerebrosides have a single sugar group linked to ceramide. The most common of these is galactose (galactocerebrosides), with a minor level of glucose (glucocerebrosides).
Galactocerebrosides are found predominantly in neuronal cell membranes. By contrast gluco-cerebrosides are not normally found in membranes, especially neuronal membranes; instead, they represent intermediates in the synthesis or degradation of more complex glycosphingolipids. |
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Glycolipid Synthesis
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Galactocerebrosides are synthesized from ceramide and UDP-galactose
Glucocerebrosides are synthesized from ceramine and UDP-glucose. |
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Globosides and Gangliosides
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Globosides represent cerebrosides that contain additional
carbohydrates, predominantly galactose, glucose or GalNAc. Lactosyl ceramide is a globoside found in erythrocyte plasma membranes. Ceramide trihexoside contains glucose and two moles of galactose and accumulates, primarily in the kidneys, of patients suffering from Fabry's disease. |
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Globosides and Gangliosides disorders
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Fabry disease is characterized by
accumulation of globosides, a reddish-purple skin rash, kidney and heart failure, and burning pain in the lower extremities. Gaucher’s disease is characterized by accumulation of glucocerebroside, liver and spleen enlargement, erosion of long bones and pelvis and mental retardation in infantile form only. |
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Gangliosides
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Gangliosides are very similar to globosides except that they also contain NANA in varying amounts.
CNS is unique in that more than 50% of the sialic acid is in gangliosides. NANA is N-acetylneuraminic acid or sialic acid. The linkage of NANA always involves the OH group on the number 2 carbon of the carbohydrate. |
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Common Gangliosides
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The specific names for gangliosides are a key to their structure. The letter G refers to ganglioside,and the subscripts M, D, T and Q indicate that the molecule contains mono-,di-, tri and quatra(tetra)-sialic acid. The numerical subscripts 1, 2 and 3 refer to the carbohydrate sequence that is attached to ceramide; 1 stands for GalGalNAcGalGlc-ceramide, 2 for GalNAcGalGlc-ceramide and 3 forGalGlc-ceramide.
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Choleratoxin
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Choleratoxin binds to GM1on
intestinal mucosal cells allowing the A subunit cell entry where it ADP ribosylates G subunit of adenylate cyclase and activates it |
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Eicosanoids
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Prostaglandins (PGs)
Thromboxanes (TXs) Leukotrienes (LTs). |
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Prostaglandins (PGs)
Thromboxanes (TXs) Leukotrienes (LTs). |
The PGs and TXs are collectively identified as prostanoids.
Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. |
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Effects of Eicosanoids
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The eicosanoids produce a wide range of biological effects on inflammatory responses (predominantly those of the joints, skin and eyes), on the intensity and duration of pain and fever, and on reproductive function (including the induction of labor). They also play important roles in inhibiting gastric acid secretion, regulating blood pressure through vasodilation or constriction, and inhibiting or activating platelet aggregation and thrombosis.
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Prostaglandin, Leukotriene, and Thromboxane begin with
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Atachidonic Acid
Easiest to stop cascade at NSAID, COX-1, COX-2 |
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PROSTAGLANDIN ACTION
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Cause constriction or dilatation in vascular smooth muscle cells
Cause aggregation or declumping of platelets sensitize spinal neurons to pain constrict smooth muscle Regulate inflammatory mediation regulate calcium movement regulate hormone regulation control cell growth |
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LEUKOTRIENE ACTION
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Mediators of allergic response
Inflammation Bronchoconstriction Increased vascular permeability |
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THROMBOXANE ACTION
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Vasoconstriction
Mobilized intracellular calcium Promotes platelet aggregation Contraction of smooth muscle |
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Classes of Prostaglandins
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Three major classes of prostaglandins: A, E, F
Classes are distinguished from the functional groups on the cyclopentane ring. |
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Series with classes of Prostaglandins
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E series contains b-hydroxy-ketone ring
F series contains 1,3 diols A series contains a,b-unsaturated ketones Numbers denote the number of unsaturated bonds in the side chains. |
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Arachidonate Synthesis Begins With
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Linoleoyl-CoA
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Synthesis of E and F Prostaglandins from FA precursors - Major Pathways
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PGE1 - Eicosatrienoic Acid - greatest amt in human body
PGE2 - Arachidonic Acid |
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Synthesis of E and F Prostaglandins from FA precursors - Minor Pathway
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Derived from Linolenic Acid
PGE3 - Eicosapentaenoic Acid |
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Prostaglandin Synthesis
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Synthesis of the clinically relevant prostaglandins and thromboxanes from
arachidonic acid. Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 which hydrolyzes arachidonic acid from membrane phospholipids. The prostaglandins are identified as PG and the thromboxanes as TX. Prostaglandin PGI2 is also known as prostacyclin. KNOW CHART - Lec30 Pg 9 |
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Prostaglandins and Throboxanes Synthesis
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The pathway is initiated through the action of prostaglandin G/H synthase, PGS. This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase.
There are 2 forms of the COX activity. COX-1 (PGS-1) is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells. |
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Prostaglandins and Throboxanes Synthesis (cont)
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COX-2 (PGS-2) is inducible and is expressed in macrophages and monocytes in response to inflammation. T
the primary trigger for COX-2 induction in monocytes and macrophages is platelet-activating factor, PAF and interleukin-1, IL-1. Both COX-1 and COX-2 catalyze the 2-step conversion of arachidonic acid to PGG2 and then to PGH2. |
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Leukotriene Synthesis
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Synthesis of the clinically relevant leukotrienes from arachidonic acid.
Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2 which hydrolyzes arachidonic acid from membrane phospholipids. The 1st step for synthesis of leukotrienes(LTs) is catalyzed by Lipoxygenase. 5-Lipoxygenase, in leukocytes, catalyzes arachidonate 5-HPETE (5-hydroperoxy-eicosatetraenoic acid). 5-HPETE is then converted to various leukotrienes that induce inflammation and asthmatic constriction of the bronchioles. LTA4 is unstable intermediate |
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Mechanism of Action of Non-Steroidal Anti-Inflammatory Drugs
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Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen, indomethacin, naproxen, phenylbutazone and aspirin, all act upon the cyclooxygenase activity, inhibiting both COX-1 and COX-2.
Because inhibition of COX-1 activity in the gut is associated with NSAID-induced ulcerations, pharmaceutical companies have developed drugs targeted exclusively against the inducible COX-2 activity (e.g. celecoxib and rofecoxib). |
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Mechanism of Action of Non-Steroidal Anti-Inflammatory Drugs (cont)
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Another class, the corticosteroidal drugs, act to inhibit phospholipase A2, thereby inhibiting the release of arachidonate from membrane phospholipids and the subsequent synthesis of eicosinoids.
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Amino Acid Metabolism
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Amino acids undergo transamination and oxidative deamination. The ammonia released by this process is transported in the form of glutamine or alanine. Ammonia gets detoxified to urea in the liver during the urea cycle. Amino acids are degraded into various compounds. They are synthesized from different intermediates of the citric acid cycle.
AA not stored in body like fats. |
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Amino Acid Pool
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-Dietary Protein
-Synthesis of body protein -Synthesis of non-protein Nitrogen containing cmpds -Conversion of AA to glucose to glycogen, FA, CO2 -De novo synthesis of nonessentail aa -Degredation of body proteins |
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Nonessential AA
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ody can supply/make them
Alanine Asparagine Aspartate Cysteine Glutamate Glutamine Glycine Proline Serine Tyrosine |
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Essential AA
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Only from diet
Arginine Histidine Isoleucine Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine |
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Why are Arginine, Methionine, & Phenylalanine essential?
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because the body does not
have the synthetic capacity to meet the demands. |
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What are methionine and phenylalanine used to produce?
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Methionine is used to
produce cysteine. Phenylalanine is used to produce tyrosine. |
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Metabolic fate of nonessential aa and histidine
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Points of entry at various steps of the TCA cycle, glycolysis, and gluconeogenesis
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Metabolic fate of essential aa plus cysteine and tyrosine
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Carbons from amino acids enter
intermediary metabolism at seven points in the glycolytic pathway and the TCA cycle. |
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The seven products of amino acid catabolism
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Oxaloacetate
a-ketoglutarate Pyruvate Fumarate Succinyl CoA Acetyl CoA acetoacetate |
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Amino acid deamination
3 Types |
The first step in catabolism of most AA is the transfer of their a-amino group to a-ketoglutarate. The products are an a-keto acid and glutamate.
All amino acids, with the exception of lysine and threonine, participate in transamination. A transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. |
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Glutamate-pyruvate aminotransferase reaction
alanin & transaminase |
Present in many tissues
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Glutamate-oxaloacetate transaminase:
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facilitates the conversion of aspartate
and alpha-ketoglutaric acid to oxaloacetate and glutamate. A transamination between alanine and aspartate must occur via coupled reaction. |
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Mechanism of action of aminotransferase
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All aminotransferases require the coenzyme
pyridoxal phosphate. Aminotransferases act by transferring the amino group of an amino acid to the pyridoxal part of the coenzyme to generate pyridoxamine phosphate. Pyridoxal phosphate is the active form of Vitamin B6 |
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Transamination: Two functions
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Occurs during degradation/catabolism of amino acids
These reactions can also be used to synthesize amino acids needed or not present in the diet. Nonessential AA are synthesized from available "root" ketoacids (with a synthetic connection to the final amino acid) by transfer of a preexisting amino group from another AA |
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Disposal of Amino Acids
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Urea Cycle
Transamination reactions transfer amino groups, oxidative deamination by glutamate dehydrogenase results in the liberation of an amino group as free ammonia. The products, a-keto acid can enter the central pathway of energy metabolism and ammonia can enter the urea cycle. |
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Step One of AA Disposal
|
Transamination(aminotransferase)
NH2 of alpha aa to a-keto acid |
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Step Two of AA Disposal
|
Oxidative Deamination (Glutamate dehydrogenase) This is a critical enzyme. This step may be reversed
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Synthesis of AA
|
Reductive Amination (glutamate dehydrogenase) to Transamination (aminotransferase)
The reaction can be used to synthesize amino acids from the corresponding alpha -keto acids. The direction of the reaction depends on the relative concentrations of glutamate, alpha ketoglutarate, and ammonia and the ratio of oxidized to reduced coenzymes (NAD+ OR NADP+). |
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Glutamate dehydrogenase:
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In liver, oxidative deamination by glutamate dehydrogenase results in the liberation of free ammonia
The sequential action of transamination and the oxidative deamination of glutamate provide a pathway whereby the amino groups of most AA can be released as ammonia. |
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Glutamate Dehydrogenase in Liver
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In liver, ammonia is incorporated into glutamate by glutamate dehydrogenase, which
also catalyzes the reverse reaction. Glutamate always serves as one of the amino acids in transaminations and is thus the “gateway” between amino groups of most amino acids and free ammonia. Is reversible |
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Nitrogen cycle
|
Bacteria Plants to
Animal diets, proteins, aa + NH3 to Human proteins |
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Transport of Ammonia
|
Transport of ammonia to the liver is mostly in the form of glutamine or alanine
Glutamine synthetase is responsible for the synthesis of glutamine from glutamate and NH3 |
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Glutamate synthesis
|
Glutamate is synthesized by the reductive amination of a-ketoglutarate catalyzed by glutamate dehydrogenase.
In addition, glutamate arises by aminotransferase reactions, with the amino nitrogen being donated by a number of different amino acids. Thus, glutamate is a general collector of amino nitrogen. |
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Glutamine Biosynthesis
|
Glutamine is produced from glutamate by the direct incorporation of ammonia; and this can be considered a nitrogen fixing reaction.
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Glutamine Synthetase Reaction
|
Role of glutamine is to carry ammonia from peripheral tissues to the liver where it is converted to ammonia by
glutaminase: glutamine + H2O -------> glutamate + NH3 |
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Form of transport of Ammonia
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Transport of ammonia is mostly in the form of glutamine or alanine
Glutamine synthetase is responsible for the synthesis of glutamine from glutamate and NH3 Glutaminase converts glutamine to glutamate and ammonia in the liver by the mitochondria excreted as urea. |
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Ammonia and blood
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Free ammonia is toxic in the blood
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Transport of ammonia
|
Second mechanism of transport involves alanine
Pyruvate is transaminated to form alanine (alanine-aminotransferase aka: glutamate-pyruvate transaminase). Alanine is transported by the blood to the liver where it is converted back to pyruvate. |
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Urea Cycle - atoms
|
Occurs in Liver
N from amino in asoartate C from bicarbonate N from ammonia |
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RXNS in Urea Cycle
|
There are 5 enzymes. 2 in mitochondria and 3 in cytosol
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Urea Cycle start and end
|
Starts with Carbamoyl Phosphate Synthase I (CPSI) in the mitochondria
Ends with fumarate |
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Allosteric Activators in Urea Cycle
|
Arginine is an allosteric activator and a co-factor
N-Acetylglutamate is an allosteric activator of CPS-1 |
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1st RXN in the Urea Cycle
|
OTC - Orinithine Transcarbomoylase
Formation of citrulline Ornthine is not in cellular proteins |
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Number of ATP's used in Urea Cycle
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4
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Intermediate precursor of urea
|
Arginase
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What in the Urea cycle for to the Citric Acid Cycle?
|
Fumarate
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Cleavage of Arginiosuccinate
|
Argininosuccinate lyase cleaves and leaves fumarate
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Oxaloacetate Fates
|
Transamination to aspartate
Conversion into glucose by the gluconeogenic pathway Condensation with acetyl CoA to form citrate Conversion to pyruvate |
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Cleavage of Arginine in Urea Cycle
|
to ornithine and urea
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Key Points to AA degredation
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1) Amino group of amino acids are transferred to alpha-ketoglutarate, forming an alpha-keto acid and glutamate via transaminase
2) Glutamate is deaminated to form ammonia and to regenerate alpha-ketoglutarate via glutamine dehydrogenase 3) Conversion and elimination of ammonia as urea via carbamoyl phosphate synthetase and the urea cycle enzymes 4) Metabolism of the carbon backbone (happens via TCA cycle) |
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Glucogenic vs. Ketogenic
|
Ketogenic:
Leu, Lys are degraded to acetyl CoA Glucogenic and ketogenic: Ile, Phe, Tyr, Trp Glucogenic: all others |
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Metabolic breakdown of individual amino acids
|
The 7 products of amino acid catabolism are:
Oxaloacetate a-ketoglutarate Pyruvate Fumarate Succinyl CoA Acetyl CoA acetoacetate |
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One-carbon metabolism
|
Tetrahydrofolate (THF)
S-adenosylmethionine (AdoMet) Biotin |
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The role of tetrahydrofolate in amino acid metabolism
|
The reduced form of folic acid
A one carbon carrier that facilitate interconversion of Methenyl: CH= Formyl: -CHO Formimino : CHNH Methylene: CH2- Methyl: CH3 |
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Tetrahydrofolate
|
N5 is the site of attachment of methyl groups
N10 is the site for formyl (HC=O) and formino-methylene (C=NH2) and methylene ( CH2 ) and methenyl (=CH ) groups to form bridges between N5 and N10. |
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Interconversion of H4Folate and Roles
in Amino Acid Metabolism |
Starts with Methionine Salvage
Ends with Tryptophan metabolism |
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Biosynthesis of S-Adenosyl Methionine (SAM)
|
AKA Adomet
Can be activated or transferred All of PO4 are lost |
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SAM
|
S-Adenosyl Methionine
SAM serves as a precursor for numerous methyl transfer reactions. Methyl group transfer from AdoMet to a methyl acceptor is irreversible. When cells need to resynthesize methionine, homocysteine methyltransferase catalyzes the transfer. (THF cofactor) |
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Synthesis of Serine
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Two Pthwys
3-phosphoglycerate as a precursor Glycine |
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Derivative of Serine
|
Decarboxylated Serine
Tri-methylated ethanolamine Ethanolamine Choline |
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Synthesis of Tyrosine
|
From phenylalanine
will go to protein or produce tyrosine phenylalanine hydroxylase is irreversible |
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Phenylketonuria
|
Missing or deficient phenylalanine hydroxylase leads to the genetic disease known as phenlyketonuria (PKU), which if untreated leads to severe mental retardation.
If the problem is diagnosed early, the addition of tyrosine and restriction of phenylalanine from the diet can minimize the extent of mental retardation. |
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AA Metabolism Disorder:
Albinism |
Defective Process: Melanin synthesis from tyrosine
Defective Enzyme: Tyrosinase Symptoms & Effects: Lack of Pigmentation. White hair, pink skin |
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AA Metabolism Disorder:
Alkaptoneuria |
Defective Process: Tyrosine degradation
Defective Enzyme: Homogentisate Dioxygenase Symptoms & Effects:Dark pigment in urine. Late developing arthritis |
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AA Metabolism Disorder:
Phenylketonuria |
Defective Process: Conversion of phenylalanine to tyrosine
Defective Enzyme: Phenylalanine hydroxylase Symptoms & Effects: Neonatal vomitting and mental retardation |
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Synthesis of Methionine and Cysteine
|
Methionine to homocysteine via methionine synthase is irreversible
Cystathionine is final product |
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Tryptophan as a precursor
|
Niacin- a precursor for NAD and NADP
Serotonin- a neurotransmitter |
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Tyrosine as a precursor
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Thyroid hormones T3 and T4
Catacholamines Dopamine, Norepinephrine, Epinephrine Melanin- a pigment of skin, hair, and eye |
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Glycine as a precursor
|
Creatine-used as high energy compound, phosphocreatine
Glutathione- tripeptide, gamma glutamyl cysteinyl glycine, reducing agent, helps remove toxic peroxides Heme-iron containing prosthetic group |
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Glutamine as a precursor
|
GABA_ g-aminobutyric acid, an inhibitory neurotransmitor
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Tyrosine and Catecholamine Synthesis
|
Tyrosine to
DOPA to Dopamine to NE to Epi |
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Synthesis of 5-HT and Tryptophan
|
Start at tryptophan and end with 5-HT and Melatonin
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Transamination of a-keto acids
|
ie: pyruvate+glutamate alanine+ a-ketoglutarate
ie: oxaloacetate +glutamate aspartate + a-ketoglutarate |
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Amidation
|
aspartate asparagine
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Synthesis of other aa
|
phenylalanine tyrosine
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Synthesis FROM other aa
|
Serine glycine
phenylalanin tyrosine methionine cysteine glutamate glutamine |
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What are purines and pyrimidines?
|
Purines and pyrimidines, often called bases, are
nitrogen-containing heterocyclic compounds with these structures. |
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Purines
|
This is the structure of a basic purine molecule. Notice the numbers on the rings. There are two ring structures.
Purine bases you will find in DNA are Adenine and Guanine |
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Pyrimidines
|
Pyrimidines have a single six sided ring structure.
Thymine, cytosine, uracil Uracil is found in RNA |
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Naming nucleotides and nucleosides
|
The purine NSs end in "-sine" : adenosine and guanosine
The pyrimidine NSs end in "-dine" : cytidine, uridine, deoxythymidine To name the NTs, use the NS name, followed by "mono-", "di-" or "triphosphate": adenosine monophosphate, guanosine triphosphate, deoxythymidine monophosphate |
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Functions of Nucleotides
|
Energy metabolism
Monomeric units of nucleic acids Physiological mediators Precursor function Components of coenzymes Coenzyme A, FAD, NAD+, NADP+ Activated intermediates SAM (AdoMet), CDP-choline (phospholipids) Allosteric effectors |
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Metabolism of Purine Nucleotides
|
Synthesis of purine nucleotides
Purine salvage Purine nucleotide interconversions GTP and tetrahydobiopterin Uric acid |
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Purine Synthesis
|
PRPP (5-phosphoribosyl-1-pyrophosphate) to PRA (5-phosphoribosylamine via N from glutamine is the commitment step
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|
Synthesis of purines requires
|
Amino acids
Glycine Glutamine (2) Aspartate CO2 One carbon units transferred via THF (2) |
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|
Atoms om the purine ring
|
See Lecture 35, Pg 10
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Regulation of Purine Synthesis
|
Is self regulating
Regulated by IMP, GMP, AMP |
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|
Purine Feedback System
|
If increase in AMOP, then negative effect on pthwy
GOUT if overproduction of IMP This is the commitment step Rate of AMP production increases with increasing concentrations of GMP; rate of GMP production increases with increasing concentrations of AMP |
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Purine Salvage Transferases
|
Adenine phophoribosyl transferase (APRTase) &
Hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) |
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|
Salvage of purine nucleobases via phosphoriboseyl transferases are
|
RXNS regulated by end product
|
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|
Interconversions of purine nucleotides
|
Amount of GDP, GTP, etc has an effect on all other compounds
|
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|
Tetrahydrbiopterin
|
Synthesized from GTP
Co-factor in many RXNS |
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Metabolism of purine nucleotides lead to
|
Uric Acid as its final product
|
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|
Too much uric acid equals
|
GOUT
|
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|
GOUT
|
Gout is a disorder characterized by high levels of uric acid in blood, as a result of either the overproduction or under excretion of uric acid.
Gout is treated with drugs such as allopurinol that inhibit xanthineoxidase Suicide inhibitors bind with xanthineoxidase |
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Synthesis of pyrimidine nucleotides
|
Carbamoyl phosphate synthase II is regulated step (carbamoyl phosphate and aspartate)
Committed step is carbamoylasparate |
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|
CPS I
|
Mitochondria
Urea Cycle Ammonia Activator: N-acetyl-glutamate |
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CPS II
|
Cytosol
Pyrimidine Synthesis g-amide group of glutamine Activator: ATP Inhibitor: UTP |
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Source of atoms for pyrimidines
|
N - glutamine amide
C- HCO3- Rest of ring - Aspartate |
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Synthesis of pyrimidines vs. purines.
|
First, the ring structure is assembled as a free base in pyrimidines, not built upon PRPP like purines.
Second, there is no branch in the pyrimidine synthesis pathway. |
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Synthesis of CTP from UTP
|
CTP Synthetase takes Uridine 5-triphosphate to Cytidine 5-triphosphate
|
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|
In De novo synthesis, the pyrimidine ring is
|
synthesized from bicarbonate, aspartate, and glutamine (or ammonium ion)
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|
Deoxyribonucleotide formation
|
Deoxyribonucleotides are formed by the reduction of ribonucleoside diphosphates.
All deoxyribonucleotides are synthesized from ribonucleotides by the enzyme ribonucleotide reductase. The enzyme is highly regulated. |
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|
Deoxyribonucleotide formation enzyme
|
ribonucleotide reductase
Ribonucleoside diphosphate to deoxyribonucleoside diphosphate |
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|
Role of ribonucleotide reductase in DNA synthesis
|
1-5 are kinase
5 is DNA polymerase |
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Synthesis of deoxythymidine nucleotide
|
Once Carbon Donor
Thymidylate Synthase Deoxthymidylate (dTMP) is formed by methylation of deoxyuridine 5’-mono Phosphate (dUMP) |
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Deoxyribopyrimidine interconversions of pyrimidine nucleotides
|
Deoxyuridine to dUMP or
Deoxyctidine to dCMP to dUMP |
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Key Point for deoxypyrimidine nucleotide synthesis
|
UMP is the precursor for all the pyrimidine nucleotides
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|
Pyrimidine nucleotides are degraded to
|
b-amino acids
|
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|
Pathways to degrade the pyrimidine nucleotides of DNA and RNA
|
RNA and DNA to Uracil
DNA to Thymine |
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|
Degredation of Uracil and Thymine
|
Uracil to b-alanine
Thymine to b-aminoisobutyrate |
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|
Nucleoside and Nucleotide Kinases
|
Nucleotide mono-, di-, and triphosphates are interconvertible
For example - UMP → UDP → UTP • Specific nucleoside (X) monophosphate kinases make nucleoside Diphosphates XMP + ATP XDP + ADP • A nucleoside diphosphate kinase, with broad substrate specificity, interconverts dinucleosides and trinucleosides (this enzyme uses both ribo- and deoxynucleosides as substrates. XDP + YTP XTP + YDP |
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|
Nucleotide function in coenzyme synthesis
|
NAD
FAD CoA |
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|
NAD in Nucleotide function in coenzyme synthesis
|
start at nicotinamide and end at NAD (nicotinamide adenine dinucleotide)
|
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|
FAD as function in nucleotide coenzyme synthesis
|
start at riboflavin
end at FAD (flavin adenine dinucleotide) |
|
|
CoA as function in nucleotide coenzyme synthesis
|
start at pantothenate
and at CoA |
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|
PRPP
|
5-phosphoriboseye-1-plyrophosphate
PRPP is the KEY molecule in: de novo synthesis of purine and pyrimidine nucleotides salvage of purine and pyrimidine bases and synthesis of NAD+. |
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|
Synthesis of PRPP
|
Ribose 5-phosphate to PRPP via PRPP synthstase Mg2+
|
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|
Some Drugs
|
dUMP can be converted to dTMP using thymidylate synthase -an enzyme targeted by anticancer drugs such as 5-flurouracil.
The regeneration of THF from DHF produced in the thymidylate synthase reaction requires dihydrofolate reductase -an enzyme targeted by the drug, methotrexate. |
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|
5-FU
|
Non-competitive antagonist
Suicide inhibitor Acts at thymidylate synthase |
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|
3 classic anti-cancer drugs
|
Purine Analog
Pyrimidine Analog Pyrimidine Analog |
|
|
Folic Acid Antagonist
|
Methotrexate
|
|
|
Acyclovir, AZT, pyrimidine
|
Acyclovir a purine analog, and AZT a pyrimidine analog are used in the treatment of HSV and HIV infections
|
