Week 14 Objectives

Question 1

Name the principal catabolites of the carbon skeletons of the protein amino acids and the major metabolic fates of these catabolites.

Answer 1

Principal catabolites of the carbon skeletons of amino acids: a-ketoglutarate, succinyl- CoA, fumarate, oxaloacetate, pyruvate, acetyl- CoA, and acetoacetyl- CoA.

Intermediates of the TCA: a-ketoglutarate, succinyl- CoA, fumarate, oxaloacetate, and pyruvate
Substrate of FAS: Acetyl- CoA and acetoacetyl- CoA

Question 2

Outline the metabolic pathways for tyrosine, phenylalanine, methionine, cysteine and branched chain amino acids, and identify reactions associated with clinically significant metabolic disorders.

Answer 2

• Phenylalanine is first converted to → tyrosine

o BH4 is a cofactor for phenylalanine hydroxylase

• Deficiency in phenylalanine hydroxylase results in →
• Phenylketonuria (PKU)
▪ Could also be caused by a deficiency in BH4

• BH4 is also required for the metabolism of tyrosine and tryptophan metabolism.
• Tyrosine becomes essential if PAH is defective

Question 3

Explain why metabolic defects in different enzymes of the catabolism of a specific amino acid’s tyrosine, phenylalanine, methionine, cysteine and branched chain amino acids) can be associated with similar clinical signs and symptoms.

Answer 3

Deficiency of tyrosine metabolism can result in:
o Tyrosinemia
▪ Loss of various enzymes in the metabolic cascade
o Alkaptonuria
▪ Loss of homgentisate oxidase

Question 4

Draw analogies between the reactions that participate in the catabolism of fatty acids and of the branched-chain amino acids.

Answer 4

BCAA: (similar B-Oxidation)

1. transamination to ketoacids using PLP
2. oxidative decarboxylation using branched chain a-ketoacid dehydrogenase complex (BCKDC similar to PDC)

Question 5

Identify the specific metabolic defects in hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria.

Answer 5

buildup of isoleucine, leucine, and valine due to deficiency in BCKDC -> MSUD

Question 6

Document the role of S-adenosylmethionine in metabolism.

Answer 6

Methionine is primarily converted to S-adenosylmethionine (SAM)
o SAM is a key methyl donor and is always in demand.
o Metabolism of SAM -> S-adenosylhomocysteine (SAH) is driven by the need for SAM
▪ SAH ->homocysteine
• It is also a substrate for the synthesis of cysteine

• Deficiencies in methionine metabolism can contribute to elevated homocysteine levels →
hyperhomocysteinemia
o Cysteine can become essential if methionine metabolism is impaired

Question 7

Recognize tryptophan metabolites serotonin, melatonin.

Answer 7

• Tryptophan can be metabolized to:

o Serotonin and melatonin

Question 8

Describe how tyrosine gives rise to norepinephrine and epinephrine.

Answer 8

Tyrosine is the substrate for the synthesis of:
o Epinephrine and norepinephrine
o Melanin
o Note: S-adenosylmethionine is needed as a methyl donor in these conversions

Question 9

Homocysteine metabolism

Answer 9

• Homocysteine metabolism can be divided to two major parts:
1. Transsulfuration
▪ homocysteine -> cysteine using Cystathionine β-synthase and cystathionine γ-lyase
• Both enzymes require PLP as a cofactor.
▪ Enzyme or cofactor deficiencies could increase homocysteine levels

2. Remethylation
   ▪ involves the remethylation of homocysteine -> methionine
   • requires B12 as a cofactor, obtains a methyl group from folate

Question 10

Cofactors

Answer 10

B12 (cobalamin)
▪ Required for remethylation of homocysteine → methionine by methionine synthase
▪ Required for the conversion of methylmalonylCoA → succinylCoA
• Deficiencies in B12 → increased levels of methylmalonylCoA

B9 (folate)
▪ Folate cycle is required to transfer a methyl group of B12 during the remethylation of
homocysteine
▪ Folate is a carbon carrier