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DEMS Unit 2.2 > Amino Acids and Protein Metabolism > Flashcards

Amino Acids and Protein Metabolism Flashcards

1
Q

Which AAs are ketogenic?

A

Leucine

Lysine

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2
Q

Which AAs are BOTH glucogenic and ketogenic?

A

Tyrosine
Isoleucine
Phenylalanine
Tryptophan

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3
Q

Hydroxyproline

A

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

Hyp in collagen increases collagen strength via H-bonding

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4
Q

Hydroxylysine

A

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

Hyl is used in collagen for interchain cross-linking

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5
Q

Scurvy

A

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

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6
Q

Protein Degradation - 3 mechanisms

A
  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)
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7
Q

y-carboxyglutamate (Gla)

A

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)

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8
Q

Pyridoxal Phosphate (PLP)

A

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

Functions by ‘holding’ the amino group during its transfer

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9
Q

N-acetylglutamate

A

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

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10
Q

Glutamate dehydrogenase

A

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

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11
Q

How are branched chain AAs metabolized?

A
  1. Branched chain aminotransferase deaminates

2. Branched chain alpha keto dehydrogenase (BCKDH)

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12
Q

Which AAs are branched?

A

Valine
Leucine
Isoleucine

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13
Q

Maple Syrup Urine Disease

A

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

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14
Q

What is the role of AAs in thyroid hormone production?

A

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

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15
Q

Porphyrins - Synthesis

A

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)

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16
Q

S-adenosylmethionine

A

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

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17
Q

Hyperhomocysteinemia

A

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

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18
Q

Homocysteinuria

A

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

19
Q

Cysteinuria

A

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

20
Q

Tetrahydrofolate (THF)

A

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

21
Q

Glutathione (GSH)

A

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)

22
Q

Role of Tryptophan in biosynthesis

A

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

23
Q

Role of phenylalanine in biosynthesis

A

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

24
Q

Hyperphenylalaninemia

A

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)

25
Q

Phenylketonuria - Etiology

A

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

26
Q

PKU Screening

A

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

27
Q

Presentation of untreated PKU

A 
Profound, irreversible intellectual disability
Microcephaly
Epilepsy
Musty body odor 
Decreased skin and hair pigmentation
28
Q

Management of PKU

A

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

29
Q

Maternal PKU Syndrome

A

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

30
Q

MSUD - Classic presentation

A 
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
31
Q

Management of MSUD

A

High calorie, BCAA-free formulas

Hemodialysis to remove BCAAs

32
Q

Tyrosinemia Type I - Pathophysiology and Diagnosis

A

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

33
Q

Tyrosinemia Type I - Presentation

A

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

34
Q

Tyrosinemia Type I - Treatment

A

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

35
Q

Urea Cycle Disorders

A

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

36
Q

Diagnosis of hyperammonemia

A

Plasma ammonia concentration > 150 umol/L with normal anion gap and glucose concentration

Plasma quantitative amino acid analysis can distinguish between specific UCDs

37
Q

Treatment of acute hyperammonemia

A

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

38
Q

Carbamoylphosphate Synthetase I Deficiency (CPS1)

A

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

39
Q

Ornithine transcarbamylase deficiency (OTC)

A

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

40
Q

N-acetylglutamate synthase (NAGS) deficiency

A

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

41
Q

Common presentations of mild urea cycle disorders

A 
Loss of appetite 
Vomiting
Lethargy
Behavioral abnormalities
Sleep disorder
Delusions / hallucinations
42
Q

Common presentations of severe urea cycle disorders

A

Infants are normal at birth but rapidly develop:

Cerebral edema 
Lethargy
Anorexia 
Hyper or hypo ventilation 
Hypothermia 
Seizures 
Coma
43
Q

Which urea cycle disorder is associated with liver damage?

A

Arginosuccinate Lyase deficiency (arginosuccinate –> arginine)

Liver biopsy shows enlarged hepatocytes and fibrosis

DEMS Unit 2.2 (9 decks)

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