Amino Acids and Protein Metabolism

Question 1

Which AAs are ketogenic?

Answer 1

Leucine

Lysine

Question 2

Which AAs are BOTH glucogenic and ketogenic?

Answer 2

Tyrosine
Isoleucine
Phenylalanine
Tryptophan

Question 3

Hydroxyproline

Answer 3

Synthesized from proline by prolyl hydroxylase, which requires ascorbic acid as a co-enzyme

Hyp in collagen increases collagen strength via H-bonding

Question 4

Hydroxylysine

Answer 4

Synthesized from lysine by lysyl hydroxylase, which requires ascorbic acid as a co-enzyme

Hyl is used in collagen for interchain cross-linking

Question 5

Scurvy

Answer 5

Ascorbic acid is required by prolyl hydroxylase and lysyl hydroxylase in the formation of Hyp and Hyl amino acids in collagen; Vitamin C deficiency leads to a disorder of collagen strength

Presents with weakened vascular basement membrane (hemorrhages, swollen gums, bruising, anemia), loss of periodontal ligament (tooth loss), pale skin, sunken eyes

Question 6

Protein Degradation - 3 mechanisms

Answer 6

1. Ubiquitin-proteasome system (ATP dependent)
2. Lysosome / Acid Hydrolysis (ATP independent)
3. Enzymatic degradation in the stomach (via pepsin) and small intestine (via trypsin [activated by enteropeptidase], chymotrypsin, carboxypeptidase A/B)

Question 7

y-carboxyglutamate (Gla)

Answer 7

Glutamate is post-translationally modified by gamma-glutamyl carboxylase to y-carboxyglutamate (Gla); this reaction is Vitamin K dependent

Gla is necessary for proper functioning of Prothrombin (pro-coagulation)

Question 8

Pyridoxal Phosphate (PLP)

Answer 8

A derivative of Vitamin B6 required for aminotransferase reactions catalyzed by ALT and AST

Functions by ‘holding’ the amino group during its transfer

Question 9

N-acetylglutamate

Answer 9

A required activator of carbamoyl phosphate synthetase I, which converts NH4, HCO3- and 2ATP to carabamoyl phosphate in the key regulated step of the urea cycle

Question 10

Glutamate dehydrogenase

Answer 10

Catalyzes the regeneration of a-ketoglutarate from glutamate, generating free NH4+ which enters the urea cycle

Allosterically inhibited by ATP and GTP under conditions of excess energy; activated by ADP and GDP

Question 11

How are branched chain AAs metabolized?

Answer 11

1. Branched chain aminotransferase deaminates

2. Branched chain alpha keto dehydrogenase (BCKDH)

Question 12

Which AAs are branched?

Answer 12

Valine
Leucine
Isoleucine

Question 13

Maple Syrup Urine Disease

Answer 13

Deficiency of branched chain alpha keto dehydrogenase complex (BCKDH); inability to metabolize Valine, Leucine, Isoleucine leads to high concentrations of branched ketoacids in the urine

Question 14

What is the role of AAs in thyroid hormone production?

Answer 14

Tyrosine is used to make T4 (prohormone) which is converted to T3 (hormone) by deiodinase

Tyrosines are also a significant component of thyroxin binding globulin (TBG) which transports T4 and T3 through the circulation

Question 15

Porphyrins - Synthesis

Answer 15

Cyclical molecules which bind Fe2+ (i.e. Heme)

Produced from Glycine and succinyl CoA

Lead inhibits enzymes in porphyrin synthesis, leading to lead poisoning (anemia)

Question 16

S-adenosylmethionine

Answer 16

Produced from methionine with consumption of ATP; functions as a methyl group donor and a high energy storage unit

Question 17

Hyperhomocysteinemia

Answer 17

Low levels of folate and B12 required for recycling of homocysteine to methionine result in elevated levels of homocysteine, which can contribute to cardiovascular disease

Treated with folate, B6, and B12

Question 18

Homocysteinuria

Answer 18

Defect in cystathione B synthase (CBS) which converts homocysteine to cystathione (and eventually to cysteine); cysteine is now essential because it cannot be produced from homocysteine

Causes intellectual disability, skeletal abnormalities, and thromboembolism

Treated with protein/methionine-restricted diet + Folate, B6, and B12 supplementation

Question 19

Cysteinuria

Answer 19

Caused by a defect in the cysteine transporter; increased concentration of cysteine in the urine leads to crystallization, formation of kidney stones, and renal failure

Treated with acetazolamide to increase solubility of cysteine in the urine

Question 20

Tetrahydrofolate (THF)

Answer 20

Synthesized from folate; used in reactions to transfer 1C groups in a variety of biosynthetic reactions

Question 21

Glutathione (GSH)

Answer 21

Contains active cysteine residues (“SH buffer”) which maintains intracellular proteins in their reduced forms and reduces hydrogen peroxide to water (anti-oxidant activity vs. ROS)

Question 22

Role of Tryptophan in biosynthesis

Answer 22

Trp is hydroxylated by tryptophan hydroxylase to produce 5-hydroxytryptophan (5-HT), requiring BH4 as a co-factor; Trp is then used to produce serotonin, melatonin, and niacin

Question 23

Role of phenylalanine in biosynthesis

Answer 23

Phe is hydroxylated to Tyr by phenylalanine hydroxylase, requiring BH4 as a co-factor

Tyr is hydroxylated by tyrosine hydroxylase to produce DOPA, requiring BH4 as a cofactor

DOPA is metabolized to dopamine, norepinephrine, and epinephrine

Question 24

Hyperphenylalaninemia

Answer 24

Caused by a deficiency in dihydrobiopterin reductase or any of the enzymes of BH4 synthesis

Results in elevated phenylalanine levels as well as decreased production of serotonin (from Trp) and catecholamines (DA, NE, Epi, from Tyr)

Question 25

Phenylketonuria - Etiology

Answer 25

Caused by phenylalanine hydroxlase (PAH) deficiency; results in intolerance to dietary intake of the essential AA phenylalanine

Question 26

PKU Screening

Answer 26

PAH deficiency can be diagnosed by newborn screening in ~100% of cases based on the presence of hyperphenylalaninemia with normal BH4 levels

Question 27

Presentation of untreated PKU

Answer 27

``` Profound, irreversible intellectual disability Microcephaly Epilepsy Musty body odor Decreased skin and hair pigmentation ```

Question 28

Management of PKU

Answer 28

Restriction of dietary phenylalanine with Phe-free medical formula; goal plasma [Phe] is 2-6 mg/dL BH4 supplementation - increases Phe tolerance Enzyme substitution - oral/injectable administration of phenylalanine ammonia lyase (PAL) Large neutral amino acid supplementation - blocks dietary absorption of Phe and transportation across the BBB

Question 29

Maternal PKU Syndrome

Answer 29

Describes the abnormalities that result from exposure of a fetus to high maternal [Phe]; includes: Congenital heart disease Intrauterine and postnatal growth retardation Microcephaly Intellectual disability

Question 30

MSUD - Classic presentation

Answer 30

``` Maple syrup odor in cerumen Ketonuria Irritability Poor feeding by 2-3 days Encephalopathy by 3-4 days Coma and central respiratory failure by 7-10 days ```

Question 31

Management of MSUD

Answer 31

High calorie, BCAA-free formulas | Hemodialysis to remove BCAAs

Question 32

Tyrosinemia Type I - Pathophysiology and Diagnosis

Answer 32

Enzymatic deficiency of fumarylacetoacetate hydrolase (FAH) Succinylacetone concentration increased in blood and urine; elevated plasma concentrations of tyrosine and phenylalanine Molecular genetic testing of 4 common FAH mutations can detect 95% of cases

Question 33

Tyrosinemia Type I - Presentation

Answer 33

Presents in infancy / first year of life with liver and kidney dysfunction, growth failure, rickets, neurologic crisis including respiratory failure Death occurs < 10 years from liver failure, neurologic crisis, or hepatocellular carcinoma

Question 34

Tyrosinemia Type I - Treatment

Answer 34

Nitisinone - blocks p-HPPD, the second step in tyrosine degradation pathway; prevents accumulation of fumarylacetoacetate and its conversion to succinylacetone; increases plasma concentrations of Tyr so dietary restriction is necessary Liver transplant

Question 35

Urea Cycle Disorders

Answer 35

Deficiency of any enzyme of the urea cycle results in the accumulation of ammonia during the first few days of life; severely affected infants are normal at birth but rapidly develop cerebral edema, lethargy, anorexia, hypothermia, seizures, and coma

Question 36

Diagnosis of hyperammonemia

Answer 36

Plasma ammonia concentration > 150 umol/L with normal anion gap and glucose concentration Plasma quantitative amino acid analysis can distinguish between specific UCDs

Question 37

Treatment of acute hyperammonemia

Answer 37

Dialysis IV administration of arginine hydrochloride and nitrogen scavenger drugs Protein restriction to limit dietary intake of nitrogen

Question 38

Carbamoylphosphate Synthetase I Deficiency (CPS1)

Answer 38

Autosomal recessive deficiency of carbamoylphosphate synthetase I Most severe urea cycle disorder; affected infants rapidly develop hyperammonemia in the newborn period and are at risk for chronic bouts of hyperammonemia throughout life

Question 39

Ornithine transcarbamylase deficiency (OTC)

Answer 39

X-linked defect in ornithine transcarbamylase, which catalyzes the conversion of carbamoyl phosphate + ornithine to citrulline In males, OTC is as severe as CPS1; 15% of females develop hyperammonemia

Question 40

N-acetylglutamate synthase (NAGS) deficiency

Answer 40

Autosomal recessive defect in the enzyme that synthesizes N-acetylglutamate from glutamate and acetylcoA; NAG is required for CPS1 activity and so symptoms mimic CPS1 deficiency

Question 41

Common presentations of mild urea cycle disorders

Answer 41

``` Loss of appetite Vomiting Lethargy Behavioral abnormalities Sleep disorder Delusions / hallucinations ```

Question 42

Common presentations of severe urea cycle disorders

Answer 42

Infants are normal at birth but rapidly develop: ``` Cerebral edema Lethargy Anorexia Hyper or hypo ventilation Hypothermia Seizures Coma ```

Question 43

Which urea cycle disorder is associated with liver damage?

Answer 43

Arginosuccinate Lyase deficiency (arginosuccinate --> arginine) Liver biopsy shows enlarged hepatocytes and fibrosis