Kinde- Nucleotide & AA Metabolism

Question 1

Define Hartnup Disease

Answer 1

Defective transport of nonpolar AA (tryptophan)

Question 2

What are the symptoms of Hartnup Disease?

Answer 2

Pellagra-like dermatosis, photosensivity, nystagmus, tremors

Question 3

Define Cystinuria

Answer 3

Defective transport of dibasic AAs (COAL). Symptoms: nephrolithiasis (kidney stones)

Question 4

Which AAs are keotgenic only?

Answer 4

Lysine & leucine

Metabolized into Acetyl CoA or Acetoacetate directly for eventua; FA synthesis

Question 5

Which AAs are keotgenic & glutogenic?

Answer 5

Phe, Ile, Trp, Tyr, Thr (PITTT)

Question 6

What do glucogenic AAs do?

Answer 6

Metabolized into pyruvate or TCA intermediates directly for eventual glucose synthesis

Question 7

Define homocystinuria (what it is, symptoms, what it affects)

Answer 7

Type I: transsulfuration (Cystathionine B-synthase, PLP from B6)
Type II/III: methylation (homocysteine methyltranferase)
Autosomal recessive enzymatic deficiencies or nutritional deficiencies (B6, B12, folic acid)
Affects eyes (lens discoloration), skeleton (long limbs), CNS (dementia), vascular (stroke)

Question 8

Define MSUD` (what it is, symptoms, what it affects)

Answer 8

Maple syrup urine disease
Deficiency in branched chain alpha-ketp acid dehydrogenase (Val, Ile, Leu)
Accumulation of toxic metabolites leads to cognitive dysfunction, failure to thrive, low tone, hallmark MS smell, limit ingestion of BCAA with diet of synthetic proteins

Question 9

Define phenylketonuria` (what it is, symptoms, what it affects)

Answer 9

Deficient phenylalanine hydroxylase (primary PKU) leads to accumulation of toxic metabolites
Cognitive malfunction, musty smell in urine
Limit dietary Phe & supplement with Tyr

Question 10

What happens in a prolonged depletion of tyrosine?

Answer 10

Production of catecholamines & melanin is affected. More profound cognitive dysfunction, pigment dilution in skin, hair, eyes

Question 11

How is ammonia removed from the muscles?

Answer 11

By alanine. Pyruvate is formed from glucose via glycolysis. Aminotransferase rxn to form Ala from pyruvate via ALT. Alanine shuttles to liver to undergo aminotransferase rxn (via ALT) to form Glu –> urea cycle via glutamate dehydrogenase

Question 12

How is ammonia removed from the brain?

Answer 12

By glutamine.

Question 13

Define hyperammonemia.

Answer 13

Ammonia toxicity from hepatic insufficiency or disorders in urea cycle
Swelling of astrocytes due to increased glutamine formation from glutamate (can lead to cerebral edema, intracranial hypertension which is most common cause of death in acute liver failure)
Autosomal recessive. with exception to deficiencies in ornithine transcarbamoylase

Question 14

What are the 4 phases of De Novo synthesis of purines?

Answer 14

Phase I: activation of ribose 5-P to active form, PRPP (upreg by Pi, downreg by GMP, AMP, IMP)
Phase II: conversion of PRPP into PRA (committed step, upreg by PRPP, downreg by GMP, AMP, IMP)
Phase III: Construction of IMP (9-step ring-constructing sequence, consumes eq. 4 ATP, downreg by methotrexate)
Phase V: IMP –> ATP & GTP

Question 15

What are the 3 phases of De Novo synthesis of pyrimidines?

Answer 15

Phase I: construction of pyrimidine ring (orotate).
-Carbamoyl phosphate synthetase II. RLS. Downreg by UMP/UTP. Upreg by PRPP
-Aspartate transcarbamoylase (ATCase). downreg by CTP
Phase II: orotate + PRPP –> UMP. defective pathway leads to orotic aciduria without hyperammonedmia
Phase III: UMP –> CTP & dTMP. dUDP loop tp keep dUTP low to prevent incorporate into DNA. Downreg by 5-fluorouracil

Question 16

What is methotrexate (therapy targeting nucleotide synthesis/antimetabolite)?

Answer 16

Antineoplastic agent used to treat cancer by targeting DNA synthesis in rapidly dividing cancer cells.
-inhibiting both purine & pyrimidine synthesis pathways

Question 17

What is fluorouracil (therapy targeting nucleotide synthesis/antimetabolite)?

Answer 17

Antineoplastic agent used to treat cancer by targeting DNA synthesis in rapidly dividing cancer cells.
-inhibits pyrimidine synthesis, specifically by targeting thymidylate synthase. Depletes dTMP –> triggers cell death. Fluorouracil reacts with N-mTHF to more tightly bind with thymidylate synthase preventing rxn w/dUMP

Question 18

What are sulfa drugs (therapy targeting nucleotide synthesis/antimetabolite)?

Answer 18

Antimicrobial agent that selectively disrupts DNA replication.

• bacteria synthesize THF using dihydropteroate synthase + PABA
• Sulfa drugs mimics PABA substrate, inhibits the enzymatic action, halts THF formation, disrupts bacterial DNA replication (pyrimidine & purine synthesis)

Question 19

What is acyclovir (therapy targeting nucleotide synthesis/antimetabolite)?

Answer 19

Antiviral agent that is a synthetic nucleoside analogue
-viral thymidine kinase preferentially phosphorylates acyclovir for incorporation into DNA synthesis, acyclovir more closely resembles guanosine, phosphorylated acyclovir inhibits viral DNA polymerase which terminates DNA replication

Question 20

Xanthine oxidase is the target for treatment of what? And why?

Answer 20

Gout because it limits production of uric acid bc hypoxanthine –> Xanthine –> uric acid

Question 21

Adensoine deaminase (ADA) deficiency is associated with what and why?

Answer 21

SCID. Leads to high adenosine & low inosine. Adenosine –> AMP & ADP & then to dADP & dATP

Question 22

A deficiency in what is associated with Lesch-Nyhan Syndrome?

Answer 22

HGPRT
Severe form of primary hyperuricemia (leads to gout, urate kidney stones, poor muscle control, severe cognitive impairment & tendency for self-mutilation)

Question 23

What do salvage pathways do & what do they dominate?

Answer 23

Nitrogenous bases recovered during nucleotide turnover can be reincorporated into nucleotides. Dominates de novo synthesis for purines

Question 24

What do APRT and HGPRT generate?

Answer 24

APRT: AMP
HGPRT: GMP or IMP