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97 Cards in this Set
- Front
- Back
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Which amino acids are both ketogenic and glucogenic?
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Phe, Tyr, Trp
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How is phenylalanine degraded?
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- Phenylalanine hydroxylase
- Uses O2 - Tetrahydrobiopterin cofactor (regenerated by NADH and dihydrobiopterin reductase) - Forms Tyr (Tyr can then be broken down into Fumarate and Acetoacetyl-CoA) |
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What causes PKU (phenylketonuria)?
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- Abnormal Phe hydroxylase
- Abnormal dihydrobiopterin reductase (to regenerate cofactor tetrahydrobiopterin) |
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What is the problem if you are unable to degrade Phe to Tyr?
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- PKU (phenylketonuria)
- High levels of Phe are toxic and cause mental retardation, seizures, growth retardation, eczema, and musty body odor - Also affects transport of other AAs by Phe competing |
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What are the two types of PKU?
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- Classical phenylketonuria = Phe hydroxylase deficiency
- Non-classical PKU = dihydrobiopterin reductase (required for synthesis of tetrahydrobiopterin cofactor) is deficient |
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Which enzymes and cofactors are used in the degradation of Tyr?
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1. Tyrosine aminotransferase (PLP & α-ketoglutarate-->glutamate)
2. p-Hydroxyphenylpyruvate dioxygenase (O2; CO2 removed) 3. Homogentisate 1,2-dioxygenase (O2; H+ removed) 4. Maleylacetoacetate isomerase 5. Fumarylacetoacetase (H2O; fumarate removed) 6. 3-ketoacyl-CoA transferase (succinyl-CoA --> succinate) End-products = fumarate and acetoacetyl-CoA |
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What is tyrosine degraded to?
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Fumarate and Acetoacetyl-CoA
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What is the first step of tyrosine degradation?
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- Tyrosine aminotransferase (PLP)
- Ammonia transferred from tyrosine to α-ketoglutarate to form glutamate - Forms p-Hydroxyphenylpyruvate |
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If the first step of tyrosine degradation (tyrosine aminotransferase) is deficient, what happens?
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- Tyrosinemia II
- Erosions of cornea, palm of hand and soles of feet - Controlled by a low-tyrosine diet |
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What is the second step of tyrosine degradation?
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- p-Hydroxyphenylpyruvate dioxygenase (coenzyme: ascorbate (vit. C))
- Consumes O2, releases CO2 - Decarboxylation, hydroxylation, and rearrangement of side chain of p-hydroxyphenylpyruvate - Yields homogentisate |
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If the second step of tyrosine degradation (p-Hydroxyphenylpyruvate dioxygenase) is deficient, what happens?
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- Tyrosinemia III (asymptomatic)
- Benign because p-hydroxyphenylpyruvate can be excreted in urine |
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What is the third step of tyrosine degradation?
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- Homogentisate 1,2-dioxygenase
- Opening of phenol ring of homogentisate - Forms maleylacetoacetate - Consumes O2, releases H+ |
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If the third step of tyrosine degradation (Homogentisate 1,2-dioxygenase) is deficient, what happens?
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- Alkaptonuria aka Black urine disease
- Homogentisate is excreted in urine (because it is not being degraded) - In presence of O2 under basic conditions forms a dark pigment - Also accumulates in soft tissue (skin and sclera) and joints, which can induce arthritis and disc calcification |
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What is the fourth step of tyrosine degradation?
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- Maleylacetoacetate isomerase
- Isomerization of maleylacetoacetate - Forms fumarylacetoacetate |
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What is the fifth step of tyrosine degradation?
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- Fumarylacetoacetase
- Hydrolyzes fumarylacetoacetate to fumarate and acetoacetate |
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What is the sixth (and final step) of tyrosine degradation?
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- 3-ketoacyl-CoA tranferase
- Acetoacetate is converted to acetoacetyl-CoA - Succinyl-CoA donates CoA group forming succinate |
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If the fifth step of tyrosine degradation (fumarylacetoacetase) is deficient, what happens?
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- Tyrosinemia I (most severe)
- Liver transplant is required to cure deficiency - Temporarily treated with administration of NTBC plus protein restricted diet low in Phe and Tyr - NTBC inhibits p-hydroxyphenylpyruvate dioxygenase leading to a build-up of p-hydroxyphenylpyruvate which can be excreted in urine - NTBC inhibits the enzyme that is deficient in tyrosinemia III (which is typically asymptomatic) |
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What are the branched chain AAs?
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- Valine
- Isoleucine - Leucine |
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What enzymes are used in the first two steps of degradation of branched chain AAs (Val, Ile, Leu)?
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- Branched chain aminotransferase (donates amino group to α-ketoglutarate and replaces with carbonyl)
- Branched chain α-keto acid dehydrogenase complex (uses CoA-SH, NAD, and CO2) replaces carboxylic acid with CoA |
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If the second enzyme (Branched chain α-keto acid dehydrogenase complex) in the degradation of branched chain AAs (Val, Ile, Leu) is inhibited, what happens?
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- Maple Syrup Urine Disease
- More common in Pennsylvania Mennonites - High excreted levels of all three branched-chain Branched chain α-keto acids gives urine maple syrup odor - Severe CNS defects including mental retardation and premature death - Tx: long term protein restricted diets supplemented with vitamin thiamin plus aggressive intervention during acute metabolic decomposition |
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After the first two steps of the branched chain AA (Val, Ile, Leu) degradation, what happens to the acyl-CoA derivatives?
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- Valine converted to propionyl-CoA and then to succinyl-CoA
- Isoleucine converted to propionyl-CoA and then to succinyl-CoA and acetyl-CoA - Leucine converted to acetyl-CoA and acetoacetyl-CoA |
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What AAs are generated from glycolysis intermediates?
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Ser (Gly & Cys), and Ala
- 3-phosphoglycerate --> Serine --> Glycine and Cysteine - Pyruvate --> Alanine |
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Which AAs are generated from TCA cycle intermediates?
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Glu (Gln, Pro, & Arg), and Asp (Asn)
- α-ketoglutarate --> Glutamate --> Glutamine, Proline, and Arginine - Oxaloacetate --> Aspartate --> Asparagine |
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What has a predictable diet of amino acids done to the enzymes used to synthesize AAs?
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- Any AA synthesis pathways that are >5 steps have been lost (know that you will be supplied with it in the diet)
- Exception: arginine requires 10 steps, however many of these steps are part of urea cycle |
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How is serine synthesized?
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- Start with 3-phosphoglycerate (glycolysis intermediate)
- Remove phosphate and add ammonia - OR from glycine (serine hydroxymethylay to transferase) |
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To synthesize serine from glycine, what enzyme and cofactors are required?
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- Serine hydroxymethyl transferase
- PLP cofactor (oxidized and phosphorylated form of B6 vitamin) - Methyl donated from N5, N10-methylene tetrahydrofolate (1C pathw |
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What is serine used to synthesize?
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- Phosphatidylserine
- Glycine - Cysteine |
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How is glycine synthesized?
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- From serine: reversal of serine hydroxy- methyltransferase (serine donates a 1C unit to tetrahydrofolate (THF) for use in 1C folate pathway)
- OR: from CO2, NH4, and N5,N10-methylene THF via glycine cleavage enzyme |
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What is glycine used to synthesize / involved in?
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- Synthesis of glutathione, porphyrin and purine synthesis
- Conjugated to bile salts for solubility |
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How does glycine act as a NT?
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Inhibitory NT
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How is cysteine synthesized?
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1. Serine + Homocysteine combine via cystathione-β-synthase (PLP cofactor; remove H2O)
2. Cystathionine cleaved by cystathionine γ-lyase (PLP cofactor; H2O used; NH4+ removed) - Forms Cysteine and α-ketobutyrate |
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What is cysteine used for?
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- Glutathione synthesis
- Used in P450 system to detoxify various molecules |
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How is alanine synthesized?
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- Starting from pyruvate
- Alanine aminotransferase (ALT) - Transfer of ammonia from glutamate to pyruvate |
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What is the function of alanine?
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- Used to transport ammonia and carbon atoms from muscle, intestine, and kidney to liver
- In liver, ammonia used for urea synthesis and carbon atoms for gluconeogenesis - Alanine also used as a NT |
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How is aspartate synthesized?
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- Starting from oxaloacetate
- Aspartate aminotransferase (AST) - Transfer of ammonia from glutamate to oxaloacetate from TCA cycle |
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What is aspartate used for?
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- Contributes 1 of 2 ammonia molecules required for urea synthesis
- Neurotransmitter - Purine and pyrimidine synthesis - Malate-aspartate shuttle |
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How is glutamate synthesized?
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- Start with α-ketoglutarate
- Free ammonia added by glutamate dehydrogenase or by direct transfer from another AA by an aminotransferase |
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What is the function of glutamate?
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- Transport NH3 into mito for Urea Cycle
- Neurotransmitter - Precursor of GABA |
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What is glutamate used to synthesize?
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- Glutamine
- Arginine - Proline - Glutathione (cofactor/antioxidant) |
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How is asparagine synthesized?
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- Start with aspartate
- Asparagine synthetase puts ammonia from glutamine on aspartate |
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What is asparagine used for?
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Availability of asparagine is crucial for synthesis of proteins w/ asparagine-linked carbohydrates
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How is glutamine synthesized?
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- Start with glutamate
- Glutamine synthetase puts free ammonia on glutamate |
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What is glutamine used for?
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- Major transport AA for ammonia from most tissues to liver and kidney
- In kidney, glutamine is important for acid-base balance - Used in synthesis of purines and pyrimidines |
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How is arginine synthesized?
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- Start with glutamate
- Converted to ornithine, then to citrulline, and then to arginine (urea cycle enzymes) |
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What is arginine used for?
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Nitric Oxide and Urea synthesis
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How is proline synthesized?
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From glutamate by several steps
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What is proline used for?
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Required in high concentrations for synthesis of rod type collagens
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How is tyrosine synthesized?
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- Start with Phenylalanine
- Phenylalanine hydroxylase adds a hydroxyl group to Phe to produce Tyr |
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What is tyrosine used for?
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- Precursor for catecholamines (dopamine, norepinephrine, epinephrine)
- Precursor for melanin pigments, thyroid hormones, triiodothyronine and thyroxine |
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What are the sources of 1C units for folate pathway?
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- Serine (major)
- Glycine - Histidine - Formate |
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How is N5,N10-methylene-tetrahydrofolate synthesized?
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- From tetrahydrofolate (THF)
+ 1C unit from serine (serine hydroxymethyl transferase) + Or 1C unit glycine (glycine cleavage enzyme) |
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What important molecules are synthesized using 1C units from tetrahydrofolate?
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- Nucleic acids
- Purine synthesis - Conversion of dUMP to dTMP - Conversion of homocysteine to methionine |
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What important molecules are synthesized using 1C units from S-adenosyl methionine?
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- Conversion of NE to Epi
- Conversion of serotonin to melatonin - Conversion of phosphatidylethanolamine to phosphatidylcholine - Conversion of guanidinoacetate to creatine - Methylate DNA (regulate gene expression) - Methylate mRNA (during maturation) |
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What happens in the S-Adenosylmethionine Pathway (SAM) Cycle?
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- Homocysteine converted to methionine (methionine synthase adds methyl group donated from N5-methyl-THF)
- N5-methyl-THF from folate pathway; THF returns to folate pathway - Methionine converted to S-adenosyl-methionine (SAM) by adenosyl transferase (ATP consumed, Pi and PPi released) - SAM donates methyl group to a variety of substrates to form S-adenosyl-homocysteine - Hydrolase removes molecule of adenosine reforming homocysteine |
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Converting homocysteine to methionine (in SAM cycle) requires what enzyme and cofactors?
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- Methionine synthase
- N5-methyl-tetrahydrofolate donates methyl group - Coenzyme B12 required |
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Converting methionine to S-adenosyl-methionine (SAM) in SAM cycle requires what enzyme?
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- Methionine adenosyl transferase
- Adenosine comes from ATP - Pi and PPi released |
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Re-generating homocysteine from consumed S-adenosyl-homocysteine (SAM after methyl donated) requires what?
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- Hydrolase
- H2O - Adenosine removed |
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What happens if there is a deficiency of methionine synthase or coenzyme B12?
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- Can trap folate in N5-methyl-THF form, causing a folate deficiency
- This causes macrocytic anemia - Can lead to elevated homocysteine levels (associated with cardiovascular disease, Alzheimer's disease, osteoporosis and bone fractures) |
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What happens if a pregnant woman has a folate of Vitamin B12 deficiency, as well as a methionine synthase deficiency?
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Neural tube defects (spina bifida or anencephaly)
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What enzyme and 1C unit donor are used in the modification of DNA and RNA?
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- Methyl transferase
- S-adenosylmethionine - Methylation of DNA decreases transcription of specific genes (abnormal DNA methylation can cause cancer) - RNA methylation associated with maturation |
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What molecules contribute to the purine molecule?
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- 2 x 1C units from formate
- 2 x amide N from glutamine - 1 x amide N from aspartate - 1 x C from CO2 - C=C-N from glycine |
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What molecules contribute to the pyrimidine molecule?
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- Aspartate (C-C-C-N)
- Glutamine amide (N) - HCO3- (C) |
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How is creatine synthesized?
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- Transfer of amidino group from arginine to glycine to form guanidinoacetate (amidinotransferase)
- 1C unit from S-adenosylmethionine (SAM) transferred by methyltransferase to form creatine |
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How is phosphatidylcholine synthesized?
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- Phosphatidylethanoloamine receives 3 x 1C units from 3 S-adenosylmethionine (SAM) molecules
- Transferred by methyltransferase |
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How is tryptophan converted to serotonin?
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- Tryptophan converted to 5-hydroxytryptophan by tryptophan hydroxylase (tetrahydrobiopterin is a cofactor; O2 oxidized to H2O)
- Aromatic amino acid decarboxylase converts 5-HT to serotonin (PLP as cofactor; CO2 released) |
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How is serotonin synthesis from tryptophan affected by PKU?
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- Dihydrobiopterin reductase is deficient in non-classical PKU
- This is important for the synthesis of tetrahydrobiopterin (a cofactor for tryptophan hydroxylase - the first enzyme in 2-step conversion of Trp to Serotonin) |
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How is melatonin synthesized?
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1. Serotonin converted with acyl-transferase
2. Methyltransferase (w/ 1C unit donated by SAM) adds a methyl group to hydroxyl group |
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What are the functions of serotonin?
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- NT and hormone
- In CNS it controls mood, sleep, and appetite - Regulates intestinal movements |
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How and where is serotonin converted to melatonin?
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- In pineal gland
- Metabolized upon activation of retinal photosensitive ganglion cells that sense loss of light towards evening - Acyl-transferase and methyl-transferase (using SAM) converts serotonin to melatonin |
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How is nicotinate synthesized?
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- From tryptophan
- Requires vitamin derivatives, FAD from riboflavin, PLP, and TPP from thiamine |
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What is nicotinate used for?
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Production of NAD and NADP
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About half of required nicotinate (for NAD and NADP) is obtained from what?
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Tryptophan
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What can tyrosine be converted to?
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Tyrosine --> Dopa --> Dopamine --> Norepiphephrine --> Epinephrine
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Which enzyme(s) are used to convert tyrosine to dopa?
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- Tyrosine hydroxylase (requires tetrahydrobiopterin and O2)
- Tetrahydrobiopterin regenerated by dihydrobiopterin reductase |
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Which enzyme(s) are used to convert tyrosine to dopamine?
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- Tyrosine hydroxylase (requires tetrahydrobiopterin and O2) makes Dopa
- Tetrahydrobiopterin regenerated by dihydrobiopterin reductase - Aromatic amino acid decarboxylase (w/ PLP) generates Dopamine |
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Which enzyme(s) are used to convert tyrosine to norepinephrine?
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- Tyrosine hydroxylase (requires tetrahydrobiopterin and O2) makes Dopa
- Tetrahydrobiopterin regenerated by dihydrobiopterin reductase - Aromatic amino acid decarboxylase (w/ PLP) generates Dopamine - Dopamine β-hydroxylase (w/ ascorbate and O2) generate NE |
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Which enzyme(s) are used to convert tyrosine to epinephrine?
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- Tyrosine hydroxylase (requires tetrahydrobiopterin and O2) makes Dopa
- Tetrahydrobiopterin regenerated by dihydrobiopterin reductase - Aromatic amino acid decarboxylase (w/ PLP) generates Dopamine - Dopamine β-hydroxylase (w/ ascorbate and O2) generate NE - Phenylethanolamine N-methyltransferase (w/ SAM) methylates NE to make Epinephrine |
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How does non-classical PKU affect dopa and dopamine synthesis?
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- Dopa and dopamine are not formed
- Deficiency of dihydrobiopterin reductase for recycling dihydrobiopterin - Dopa can cross blood-brain barrier so is given to Parkinson's patients and non-classical PKU patients |
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Where is tyrosine converted to dopa and dopamine?
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Brain, nerves, and adrenal medulla
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What is the function of norepinephrine?
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- Stimulates attention and focus in the brain
- Stimulates heart rate - Stimulates metabolism of fats for energy and muscle readiness |
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What is the function of epinephrine?
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- Increases cAMP production
- Induces vasodilation in various organs - Also stimulates gluconeogenesis in liver |
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How is melanin synthesized?
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- Tyrosine converted to dopa and dopaquinone via tyrosinase
- Dopaquinone is converted to eumelanins and pheomelanins |
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What is the function of melanins?
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Pigments in eye, hair and skin
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What can lead to albinism?
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- Defect in conversion of tyrosine to melanin pathway (commonly tyrosinase)
- Autosomal recessive |
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How are the thyroid hormones synthesized?
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- Start with tyrosine residues on protein thyroglobulin
- Iodination by Iodoperoxidase followed by proteolysis to form Thyroxine (T4) and triiodothyronine (T3) |
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What is the function of the thyroid hormones (thyroxine, T4, and triiodothyronine, T3)?
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- Bind nuclear recepters and regulate expression of genes
- Increases rate of metabolism by stimulating fat mobilization and oxidation - Enhances gluconeogenesis and glycogenolysis - Required for normal development of brain and growth of children |
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How is GABA synthesized?
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Glutamate converted to GABA by glutamate decarboxylase (PLP; CO2 removed)
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What is the function of GABA?
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Inhibitory NT that if deficient can cause epileptic seizures
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How is Histamine synthesized?
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Histidine converted to Histamine by Histidine decarboxylase (PLP; CO2 removed)
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What is the function of Histamine?
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Stimulates release of HCl in stomach and released by mast cells and basophils in allergic reaction causing vasodilation
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Which AAs contribute to the synthesis of glutathione (GSH)?
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- Glutamate
- Cysteine - Glycine - γ-Glu-Cys-Gly (isopeptide bond between γ-carboxyl group of glutamate and α-amide bond of cysteine |
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What are the two forms of glutathione?
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- Reduced form: GSH
- Oxidized form: GSSG |
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How can the two forms of glutathione be interconverted?
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Glutathione reductase (using NADPH from PPP) reduces oxidized form of glutathione
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What is the function of reduced glutathione (GSH)?
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Antioxidant and cofactor in enzymatic reactions; important in detoxification of drugs including acetaminophen
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How is Nitric Oxide synthesized?
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- Arginine converted to NO and Citrulline by NO synthase
- Requires NADPH and molecular O2 - Tetrahydrobiopterin is a cofactor |
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What is the function of Nitric Oxide?
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Reactive free radical that kills bacteria and functions as a vasodilator and NT
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What happens to the citrulline that is synthesized from the conversion of arginine to nitric oxide?
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Recycled to arginine in most cells using argininosuccinate synthetase and argininosuccinate lyase
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