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99 Cards in this Set
- Front
- Back
- Phosphoglycerate
- Pyruvate - Oxaloacetate - alpha-ketoglutarate |
Nonessential amino acids are derived from these glycolytic and TCA intermediates
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- Pyruvate
- a-KG - Fumarate - Oxaloacetate - Succinyl CoA - Acetyl CoA - Acetoacetate |
7 metabolic intermediates derived from the 20 amino acid degradation
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______ can be synthesized from the glycolytic intermediate 3-phosphoglycerate.
3-PG is oxidized, trasaminated by glutamate, and dephosphorylated |
Serine
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_____ and ______ can be derived from serine.
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Glycine and cysteine
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________ can be produced from serine by a reaction in which a methylene group is transferred to tetrahydrofolate (FH4)
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Glycine
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_______ derives its carbon and nitrogen from serine.
The essential amino acid methionine supplies the sulfur |
Cysteine
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_______ can be derived by transamination of pyruvate
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Alanine
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_______ can be derived from oxaloacetate by transamination
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Aspartate
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______ is produced from aspartate by amidation
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Asparagine
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______ is derived from alpha-ketoglutarate by the addition of NH4+ via the glutamate dehydrogenase reaction or by transamination.
Glutamine, proline and arginine can be derived from _________ |
Glutamate
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__________ is produced by amidation of glutamate
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Glutamine
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_______ and ________ can be derived from glutamate semialdehyde.
GS is formed by reduction of glutamate |
Proline and arginine
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______ can be produced by cyclization of glutamate semialdehyde
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Proline
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_________, via three reactions of the urea cycle, can be derived from ornithine, which is produced by transamination of glutamate semialdehyde
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Arginine
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________ is syntehsized by hydroxylation of the essential amino acid phenylalanine in a reaction that requires tetrahydrobiopterin.
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Tyrosine
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- Lysine
- Isoleucine - Threonine - Tryptophan |
These four amino acids can form acetyl CoA.
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- Phenylalanine
- Tyrosine |
These amino acids can form acetoacetate
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Leucine
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Degraded to form HMG-CoA, which can be turned into acetoacetate or acetyl-CoA.
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- Threonine
- Isoleucine - Methionine - Valine |
These four amino acids form Propionyl CoA
Propionyl CoA -> Methylmalonyl CoA -> Succinyl CoA |
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This carrier of one-carbon groups transfers the most oxidized form, from CO2
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Biotin
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- Tetrahydrofolate (FH4)
- Vitamine B12 - S-adenosylmethionine (SAM) |
Transfers one-carbon units less oxidized than CO2
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_______ is the primary one-carbon carrier in the body.
Attachment of these one-carbon groups to ___ are referred to as the one-carbon pool. |
Tetrahydrofolate, FH4
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Methotrexate is used in cancer chemotherapy to block nucleotide synthesis, (which involve FH4 derivatives), especially the formation of thymidine.
It is also used to treat various forms of arthritis |
Medicinal uses of Methotrexate.
Blocks reduction step of DHF reductase. Methotrexate is an analog of dihydrofolate (thus, it is a competitive inhibitor of dihydrofolate reductase) |
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This is the only non-essential amino acid that is glucogenic and ketogenic
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Tyrosine
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- Isoleucine
- Threonine - Phenylalanine - Tryptophan |
Essential amino acids that are ketogenic and glucogenic
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- Histidine
- Methionine - Valine |
Essential amino acids that are glucogenic only
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- Leucine
- Lysine |
Essential amino acids that are ketogenic only
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1. Active form is tetrahydrofolate (FH4)
2. FH4 - carries the one carbon pool 3. Required in diet 4. Deficiencies seen in alcoholics 5. Deficiencies in pregnant women - risk of neural tube defects |
Folic acid
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- Serine (major source)
- Glycine - Histidine (via FIGLU) - Tryptophan (via formate) |
Sources of 1-carbon units
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- dTMP
- Serine, derived from Glycine - Purines - B12-CH3 |
Recipients of 1-carbon units
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1. Required in the diet (Liver stores up to 6 years supply)
2. Active part is the cobalt atom coordinated to the corrin ring - Reacts with carbon of a methyl group (methylcobalamin) or deoxyadenosine (deoxyadenosylcobalamin) 3. Two reactions in the body: a. Rearranges the methyl group of methylmalonyl CoA to form succinyl CoA - Part of the degradation route for the conversion of carbons from: - Valine - Isoleucine - Threonine - Methionine b. Transfers a methyl group to homocysteine forming: - Methionine |
Vitamin B12 (Cobalamin)
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SAM is produced from methionine and ATP
Transfers methyl groups to precursors that form the following: - Creatine - Phosphatidylcholine - Epinephrine - Melatonin - Methylated nucleotides |
S-Adenosylmethionine (SAM)
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Biological roles of _______ transaminase
1. Protein synthesis 2. Transports nitrogen from peripheral tissue to the liver (2nd highest circulating amino acid) 3. Major gluconeogenic amino acid - serves as a carbon source for glucose. |
Alanine Transaminase (ALT)
Favors Alanine and a-KG in muscle. Favors pyruvate and glutamate in liver |
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Major sites of serine synthesis?
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- Liver
- Kidney |
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1. Protein synthesis
2. Component of: a. phsphatidylethanolamine b. phsphatidylserine c. sphingolipids (PLP-dependent decarboxylation) 3. Serves as a carbon source for glucose 4. Synthesis of acetylcholine 5. Synthesis of cysteine 6. 1-carbon units 7. Synthesis of glycine |
Biological roles of serine
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Increased serine levels
- Repression of 3-phosphoglycerate dehydrogenase - Serine inhibits phosphoserine phosphatase Decreased serine levels - Induction of 3-phosphoglycerate dehydrogenase - Release of phosphoserine phosphatase inhibition |
Regulatory mechanisms of body serine levels.
Note: most protein regulation is similar to this. |
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- Serine and its metabolites (pyruvate and glycine) are precursors to sphingolipids and phospholipids.
- SAM methylates phosphatidylethanolamine to produce phosphoatidylcholine - Hydrolysis of phosphatidylcholine releases choline. - Acetylation of choline generates acetylcholine |
Key points on specialized products from serine
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1. Protein synthesis
2. 1-Carbon pool 3. Synthesis of purines 4. Synthesis of porphyrins 5. Synthesis of glutathione 6. Synthesis of creatine 7. Sythesis of glycine conjugated bile salts |
Biological roles of glycine
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- Gly, Arg, SAM and ATP are used to make creatine phosphate
- Kinase reaction is reversible - Creatine and creatine phosphate are found in muscle and brain |
Synthesis of Creatine and Creatine phosphate.
Note: creatine phosphate is very high energy, so high that it is reversible to form creatine and ATP. |
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- Creatinine has no known function
- The amount of creatine produced is related to muscle mass. - The level of creatinine cleared by the kidneys is a measure of renal function |
Creatinine is the result of spontaneous creatine phosphate cyclization.
The ratio of compound/creatinine is measured for clinical use. |
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- Absense of transamination reaction which converts glyoxalate back to glycine.
- Absence of TPP - Results in renal failure |
Type I primary oxaluria
Causes build up of calcium oxalate, kidney stones. |
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- Characterized by severe mental retardation and epilepsy.
- Patients often die in infancy. Deficiency in glycine enzyme complex. - Increase NT concentration along with formation of kidney stones. - NT is inhibitory. |
Nonketotic hyperglycinemia
Treatment - sodium benzoate: reacts with glycine to form hipurate. |
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1. Glutathione
2. Sulfur metabolism 3. Protein biosynthesis 4. Taurine 5. Taurine conjugated bile salts |
Biological roles of cysteine
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What is the major degradation destination for methionine and homocysteine?
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Degradation into Succinyl CoA
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In this environment, you are likely to find cysteine and homocysteine floating around.
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Intracellular / Reducing environment
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In this enviornment, you are likely to find cystine and homocystine floating around.
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Extracellular / Non-reducing environment
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- Group of disorders involving defects in the metabolism of homocysteine
- Autosomal recessive disorder - High plasma and urinary levels of homocysteine - High levels of methionine (cystathionine synthase or cystathionase) - Low levels methionine (vitamin B12, folate, N10-methylene-FH4 reductase) - Low levels of cysteine (vitamine B6, cystathionine synthase, cystathionase) |
Homocystinuria
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Vitamin B6 deficiency
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Homocystinemia
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Most common cause of homocystinuria is a genetic defect in ____________ synthase
Major clinical manifestations - Lens dislocation - Osteoporosis - Mental retardation - Vascular occulsions |
Defect in cystathionine synthase
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- Benign
- Due to increased Km for methionine. - Increased met requirement. |
Hypermethioninemia
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Specialized Product - Comes from breakdown of what amino acid?
3'phospoadenosine-5'-phosphosulfate (PAPS) - Transfers sulfate groups to biological molecules (sulfur metabolism) |
Product of cysteine breakdown
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1. Protein synthesis
2. Contributes 2nd nitrogen for urea formation a. Accepts nitrogen from glutamate via transmination reaction and eliminates nitrogen via arginino-succinate synthetase reaction. 3. Neurotransmitter 4. Precursor for synthesis of: a: Asparagine b. Purines c. Pyrimidines |
Biological roles of aspartate
Liver favors aspartate formation. Other tissues favor OAA and glutamate formation |
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Some leukemic cells have lost the ability to synthesize asparagine.
What is the treatment? |
Supplementing with exogenous asparaginase.
Asparagine reacts via a deamidation reaction that hydrolyzes and cleaves off NH4+, forming aspartate. |
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Amidotransferase reactions are unique in that they are always....
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irreversible and require ATP
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The only amino acids to undergo deamidation reactions
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Asparagine and glutamine
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- Aspartate (minor)
- Tyrosine - Phenylalanine |
Amino acids that produce fumarate
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- Protein biosynthesis
- Production of tyrosine |
Two fates of phenylalanine
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- Required for rign hydroxylations (ie. Tyrosine and neurotransmitters)
- Synthesized from GTP |
Tetrahydrobiopterin (electron carrier)
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1. Protein biosynthesis
2. Precursor of: a. melanins b. catecholamines c. thyroid hormones Tetraiodothyroinine (T4) and Triiodothyronine (T3) i. Secreted by thyroid acinar cells ii. Control rate of oxidation in cells |
Biological roles of tyrosine
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- Enzymes responsible for inactivation and degradation of catecholamines.
- reactions can occur in any order - Final products: a. 3-methoxy-4-hydroxymandelic acid (epinephrine, norepinephrine) b. Homovanillic acid (dopamine) |
Monoamine oxidase (MAO)and Catechol-O-methyltransferase (COMT)
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Complex mixture of biopolymers derived from tyrosine.
Produced in melanocytes Passed to surrounding keratincytes. |
Melanin
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Eumelanin
- Brown and black pigments found in hair and skin (more abundant in peoples with dark skin) Pheomelanin - Cysteine derivatives of eumelanin and imparts a yellow to reddish hue (more abundant in fair-skinned peoples) |
Two broad categories of melanin
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What enzyme is responsible for conversion of tyrosine to melanin?
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Tyrosinase
Cofactor: Cu2+ Tyrosine -> DOPA -> Dopaquinone -> Melanin |
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1. Protein synthesis
2. Eliminates nitrogen a. Collects amino nitrogen via transamination reaction - Predominant amino acid / a-ketoacid pair is glutamate/a-ketoglutarate b. Urea formation - Contributes 1st nitrogen to urea formation - Contributes nitrogen to aspartate 3. Anabolic role - Donates amino group for formation of other amino acids (transamination) 4. Excitatory neurotransmitter 5. Precursor for synthesis of: a. glutamine b. Proline c. Arginine d. Ornithine which gives rise to polyamines e. Glutathionine, serves as a cellular reductant* f. g-carboxyglutamate, critical amino acid of blood clotting proteins g. g-aminobutyric acid (GABA), an inhibitory neurotransmitter h. Purine |
Biological roles of glutamate
Glutamate and aspartate are excitatory neurotransmitters |
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- Major inhibitory neurotransmitter in CNS
- GABA receptors are Cl- channels. - Recycled neurotransmitter (remember, catecholamines are not!) |
GABA
Enzyme: Glutamate decarboxylase (PLP) Vitamin B6 deficiency = Convulsions (glutamate requires PLP for decarboxylation) Drugs (eg benzodiazepines) enhance the effects of GABA are useful for treating epilepsy and depression. |
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Histidine is an essential amino acid.
Histidine -> FIGLU -> Glutamate |
Glutamate cannot form histidine.
Important because histamine is a key neurotransmitter. |
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1. Made mainly in the liver
2. Protective reductant a. Reduces radicals and peroxides 3. Conjugation reactions to detoxification |
Glutathione (y-glutamylcysteinylglycine)
Tripeptide composed of Glutamate, Cysteine and Glycine. Remember that bond between cysteine and glutamate? are not peptide bonds |
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1. Protein synthesis
2. Precursor of: a. Asparagine b. Purines and pyrimidines 3. Nitrogen transport 4. Source of ammonia for urea formation 5. Excretion of ammonia into lumen of the renal tubule to buffer the urine (major role of kidney glutaminase) |
Biological Roles of glutamine.
Glutamate (product of glutamine degradation) follows GNG pathway |
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Essential in children.
Required to support growth Adequate amounts are released to carry out the biological role in adults. |
Arginine (adult nonessential)
Arginine cleaved by arginase to generate urea and ornithine - Ornithine levels higher than required for urea. i. Converted to either glutamate or proline |
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_____ _____ has been implicated in a wide range of physiological and pathphysiological events including vasodilation (smooth muscle)
a. Activates guanylyl cyclase leading to increases in [cGMP] b. Sildenafil (Viagra): inhibits phosphodiesterase which converts cGMP to GMP |
Nitric oxide
A signal molecule that comes from arginine and is converted to citrulline and NO. |
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Production of this molecule is quite unusual.
- Essential when dietary arginine is low or arginine synthesis is lacking. Precursor of citrulline and polyamines. |
Ornithine
(product of proline degradation) |
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- Degradation of ______ is the reverse of synthesis and occurs in mitochondria.
- Glutamate is produced - Different enzymes are used - Some of the glutamate semialdehyde makes ornithine |
proline
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1. Protein synthesis
2. Precursor of hydroxyproline |
Biological roles of proline
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- Putrescine has a foul odor
- Spermidine and spermine were isolated from semen - An early signal for cell replication is elevated levels of ornithine decarboxylase - Polyamines are highly cationic and are important for DNA synthesis and regulation of the replication process. - Polyamine synthesis is linked to SAM and SAM decarboxylase - Polyamines regulate SAM decarboxylase activity |
Polyamines and their properties
Synthesis requires ornithine and SAM |
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Since DNA is negatively charged, these molecules are thought to aid in replication based on their postive charge.
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Important property of polyamines
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- Acceptor of carbamoyl phosphate in the urea cycle
- Precursor for the synthesis of polyamines - Precursor for the synthesis of citrulline, arginine and proline |
Roles of Ornithine
Production of ornithine from glutamate is unusual - When dietary arginine is limited |
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When arginine levels are high, ornthine will be produced.
- Ornthine levels rise and semialdehyde accumulates, which inhibits ornthine transaminase. |
Usual direction of ornthine transaminase is in the direction of glutamate semialdehyde.
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- Serine
- Threonine - Histidine - Glycine - Methionine |
Deamination reactions
All occur in the liver |
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Common compound found in skin and sweat.
Product of histidine breakdown. |
Urocanate
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Compound that donates carbons to FH4 pool
Folate deficiency, it gathers in the urine. |
FIGLU
It is the precursor to glutamate. |
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- Synthesized and released by mast cells
- Mediator of allergic responses: vasodilatation and bronchoconstriction (H1 receptors) a. H1 Blockers: Diphenhydramine (Benadryl), Loratidine (Claritin) - Stimulates secretions of gastric acid (H2 receptors) a. H2 Blockers: Cimetidine (Tagamet), ranitidine (Zantac) |
Histamine
Synthesized by Histidine decarboxylase (PLP) Neurotransmitter |
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Metal binding domain of:
- Hemoglobin - Cytochromes - Chlorophyll |
Porphyrins
Formed from succinyl CoA and Glycine |
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What enzyme turns L-methymalonyl CoA into succinyl CoA?
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Methylmalonyl CoA mutase.
Vitamin B12 linked enzyme. Turns a branched structure (methylmalonyl CoA) to an unbranched enzyme (succinyl CoA) |
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Primary pathway for serine/threonine degradation.
Produces free NH3 - Source of ammonia for urea cycle |
Serine/threonine dehydratase.
PLP |
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Branched Chain Amino Acid:
Generates: - Succinyl CoA - 3 NADH - 1 FADH2 |
Valine
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Branched Chain Amino Acid:
Generates: - Acetyl CoA - Succinyl CoA - 3 NADH |
Isoleucine
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Branched Chain Amino Acid:
Generates: - Acetyl CoA and acetoacetate. - 1 NADH - 1 FADH2 |
Leucine
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Catabolism of BCAAs (Val, Iso, Leu) is carried out by almost all tissues
- 25% of the amino acids of a protein are BCAA Energy generation BCAAs can be converted to TCA intermediates Major precursors of glutamine. |
Importance of BCAA's.
Brain: - BCAA's produce glutamine, a source of nitrogen for neurotransmitter synthesis during fasting. |
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Roughly 20% of the ATP supply in a resting muscle comes from BCAA oxidation
- Synthesizes glutamine, which effluxes from the muscle a. Highest rate of BCAA oxidation occurs under conditions of acidosis b. Glutamine production and its degradation in the kidney increase pH |
Skeletal muscle BCAA catabolism.
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Tryptophan reduces the dietary requirement of niacin
Insufficient dietary levels of niacin and Trp result in _______. Symptoms are: - dermatitis - diarrhea - dementia |
Pellegra
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- regulates sleep, mood & appetite (forms in brain)
- platelet aggregation & vasoconstriction (forms in platelets) - smooth muscle contraction |
Serotonin's function as a neurotransmitter
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- Depression, migraines, schizophrenia & obsessive compulsive disorders
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Serotonin is used to treat these disorders
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The antidepressant, Prozac, inhibits reuptake of ________, thereby prolonging the ______ presence in the synaptic cleft
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serotonin
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Produced by the pineal gland in response to light-dark cycle
blood levels rise at night. Possible roles: - Organizing seasonal and circadian rhythms - Regulating reproductive functions |
Melatonin roles.
Defect in dihydrobiopterin reductase (nonclassic PKU) leads to decreased synthesis of serotonin and melatonin. |
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Transamination of this amino acid does not require PLP.
Glutamate receives the episilon amine group. |
Lysine.
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This molecule is an intermediate of lysine catabolism
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Saccharopine
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On proteins – e-amino group of lysine is trimethylated
- When protein is hydrolysed, e-N-trimethyllysine is liberated - e-N-trimethyllysine is converted to carnitine |
Carnitine is required for transport of fatty acids into mitochondria
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1. Amino acids are derived from dietary proteins, body proteins and amino acid biosynthesis
2. Amino acid NH3 is removed 3. Amino acid carbon skeleton is converted inot a major metabolic intermediate 4. Amino acids are used to synthesize nitrogen-containing compounds. |
Properties of amino acids
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- Essential amino acids come from the diet.
- Amino acids are not stored - Requirements of amino acids a. Protein synthesis i. Proteins are essential for body function b. synthesis of other biomolecules (precursor function) c. Major carbon source for gluconeogenesis i. High protein and low carbohydrate intake ii. Fasting, not prolonged fasting - Excess amino acids are degraded. - Defects in amino acid metabolism lead to many metabolic disease |
Metabolism of amino acids
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