5th Unit / Ch 20 Amino Acid Degradation and Synthesis

Question 1

Carbon Skeleton Catabolism 20 1.1

Which vertical column (A, B, or C) shown would most appropriately be labeled
“(Solely) Ketogenic Amino Acids”?

Answer 1

Column C contains the two solely ketogenic amino acids.

Question 2

Carbon Skeleton Catabolism 20 1.2

Which horizontal row (1 or 2) would most appropriately be labeled “Essential Amino Acids”? What does it mean for an amino acid to be essential?

Answer 2

Row 2 contains the nine essential amino acids, which are the amino acids that cannot be synthesized (or synthesized in sufficient quantities) by humans.

Question 3

Carbon Skeleton Catabolism 20 1.3

The pathways for catabolism of the C-skeletons of amino acids converge to form what seven intermediate products?

Answer 3

Catabolism of the C-skeletons of amino acids produces TCA intermediates
(A-KG, succinyl CoA, fumarate, and OAA) and pyruvate from the glucogenic amino acids, and

acetoacetate (or its derivative acetyl CoA) from the ketogenic
amino acids.

Question 4

Carbon Skeleton Catabolism 20 1.4

Asparaginase is used to treat childhood acute lymphoblastic leukemia (ALL ). What is the biochemical basis of this treatment?

Answer 4

Asparaginase (from bacteria) is a treatment for ALL because it deamidates circulating Asn to Asp. Rapidly dividing leukemia cells require Asn for growth and have limited capacity to synthesize it.

Question 5

Carbon Skeleton Catabolism 20 2.1

Why might FIGlu, an intermediate in the catabolism of His, as shown, be found in the urine of individuals deficient in folic acid (folate)?

Answer 5

N-formimino glutamate FIGlu reacts with THF to form N 5 -formimino-THF + Glu.

If folate (and, consequently, THF) is deficient, FIGlu accumulates and is excreted in the urine.
[Note: The FIGlu excretion test has been used in the diagnosis of folate deficiency.]

Question 6

Carbon Skeleton Catabolism 20 2.2

What is the function of THF?

Answer 6

THF is a carrier of one-C groups (attached to N5, N10, or both N5 and N10 of the molecule) in oxidation states that range from formyl to methyl.
[Note: N10 -formyl- THF is used in synthesis of the purine ring; N5, N10 -methylene- THF is used in the synthesis of dTMP from dUMP; and N5 -methyl- THF is used in the remethylation of Hcy to Met, a reaction that also requires vitamin B12. This remethylation reaction is the only time THF carries and donates a methyl group.] THF is made from folate in a two-step, NADPH-requiring reaction catalyzed by DHFR.

Question 7

Carbon Skeleton Catabolism 20 2.3

How is folate deficiency manifested clinically?

Answer 7

Folate deficiency presents as a megaloblastic anemia (a type of macrocytic anemia ) in which cell growth occurs without cell division because of decreased availability of the purines and the dTMP needed for DNA synthesis.

[Note: Vitamin B 12 deficiency presents in a similar manner.]

Question 8

Sulfur-Containing Amino Acids 20 3.1

What is the function of SAM, produced by the metabolism of Met, as shown?

Answer 8

SAM (like THF) is a one-C carrier, but (unlike THF) SAM carries only methyl groups, which are transferred by
methyltransferases to acceptors such as norepinephrine, PE, DNA, and RNA.

Question 9

Sulfur-Containing Amino Acids 20 3.2

Cys, produced from the sulfur of Methionine and the C-skeleton of Serine (shown), can be desulfurized to pyruvate. What is an
important use of the sulfate released in this process?

Answer 9

The sulfate released can be used to synthesize
3’-phosphoadenosine-5’-phosphosulfate (PAPS), an activated sulfur
donor to acceptors such as glycosaminoglycans

Question 10

Sulfur-Containing Amino Acids 20 3.3

Why is homocystinuria a concern? What role do vitamins B6, B12 , and folate play in maintaining low homocysteine levels?

Answer 10

Homocystinuria, caused by elevated Hcy levels, promotes endothelial dysfunction and is an independent risk factor for occlusive vascular disease. Hcy is kept low by (1) conversion to Cys, a two-step, B6 -dependent process (shown) catalyzed by cystathionine synthase and cystathionase, and (2) remethylation to Met, a THF- and B12 -requiring reaction catalyzed by

methionine synthase. As the levels of vitamins B6, B12,
and folate↓, Hcy levels↑. Mild elevations of Hcy are seen in a small percentage of individuals, but large elevations are rare and are primarily seen in cystathionine B-synthase deficiency.

Question 11

Branched-Chain Amino Acids 20 4.1

What coenzymes are required by Branched-chain α-keto acid dehydrogenase BCKD, the enzyme that oxidatively decarboxylates the a-keto acid derivatives of the BCAAs, as shown? What other enzymes also require them?

Answer 11

BCKD, a mitochondrial enzyme, requires NAD+ and CoA as cosubstrates and thiamine pyrophosphate, lipoic acid, and FAD as prosthetic groups.

PDH and a-KGD are the other mitochondrial a-keto acid dehydrogenase complexes that require this group of coenzymes.

Question 12

Branched-Chain Amino Acids 20 4.2

In addition to Val and Ile, what other amino acids are metabolized to propionyl CoA and, ultimately, succinyl CoA?

Answer 12

In addition to Val and Ile, Met and Thr are metabolized to propionyl CoA. Biotin-dependent Propionyl CoA carboxylase converts Propionyl CoA to Methylmalonyl CoA, which is converted to succinyl CoA by a B12 -dependent mutase.

The other B12-requiring reaction in humans is the remethylation of Hcy to Met.
[Note: FAs with an odd number of C atoms produce propionyl CoA in the final round of B-oxidation.]

Question 13

Branched-Chain Amino Acids 20 4.3

Why are individuals with maple syrup urine disease (MSUD), a rare

AR disorder caused by BCKD deficiency,
at particular risk during periods of physiologic stress?

Answer 13

Physiologic stress triggers skeletal muscle proteolysis to meet increased energy needs. Because Val and Ile provide glucose (from the metabolism of succinyl CoA to glucogenic Ala) and Leu and Ile provide acetyl CoA, these energy sources will be in decreased supply in individuals with MSUD, putting them at
particular risk during periods of physiologic stress. Additionally, elevated Leu can cause neurologic damage.
[Note: BCKD deficiency confers a maple syrup–like odor to body fluids.]

Question 14

Aromatic Amino Acids 20 5.1

What coenzyme is required by the Phenylalanine
hydroxylase PAH reaction shown?

Answer 14

Tetrahydrobiopterin THB (BH4), made from guanosine
triphosphateGTP, is the coenzyme for the phenylalanine hydroxylasePAHreaction. Its deficiency results inhyperphenylalaninemia and decreased Tyr production.

Question 15

Aromatic Amino Acids 20 5.2

What other enzymes of amino acid metabolism require the coenzyme Tetrahydrobiopterin THB (BH4)?

Answer 15

BH4 is also used by tyrosine and tryptophan hydroxylases. Its deficiency
decreases synthesis of the catecholamines from Tyr and serotonin from Trp. Treatment includes replacement therapy.

[Note: Use of BH 4 by aromatic amino acid hydroxylases (and by NOS that synthesizes NO from Arg) is in contrast to
the use of PLP in most other reactions involving amino acids.]

Question 16

Aromatic Amino Acids 20 5.3

What is the cause of phenylketonuria ( PKU ), and how is it treated? Why are the CNS effects of
PKU now rarely seen?

Answer 16

• *PAH deficiencies** cause PKU, which is characterized by a “mousey” odor. Treatment includes Phe restriction and supplementation with the now-essential Tyr. Newborn screening programs have allowed early diagnosis and treatment of
• *PKU**, preventing the microcephaly, intellectual disability, and seizures, characteristic of the untreated deficiency. Because Phe is teratogenic, women with PKU can give birth to children with anatomic anomalies if Phe levels are not controlled ( maternal PKU syndrome).

Question 17

Aromatic Amino Acids 20 5.4

What is the clinical consequence of tyrosinase deficiency?

Answer 17

Lack of tyrosinase, which is required for the synthesis of melanin from Tyr, causes oculocutaneous albinism. These defects result in the partial or full absence of pigment from
the skin, hair, and eyes.

Question 18

Aromatic Amino Acids 20 5.5

What are the causes and clinical consequences of alkaptonuria?

Answer 18

Deficiency of homogentisic acid oxidase of Tyr catabolism causes alkaptonuri. Symptoms include formation of a blue-black pigment-like polymer (ochronosis) in connective tissue (and urine) and early-onset arthritis.