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SFM Exam 2 > Amino Acid Metabolism & Urea Cycle > Flashcards

Amino Acid Metabolism & Urea Cycle Flashcards

1
Q

Nitrogen Balance = Consumption - Excretion

A

N Balance = [Protein N intake (g/24hr)] - [UUN + 4g]

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2
Q

When N Excretion > N Consumption

A
  • inadequate protein intake
  • lack of essential amino acids
  • physiological stress
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3
Q

When N Consumption > N Excretion

A
  • pregnancy

- times of growth (childhood)

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4
Q

What 3 things supply free amino acids?

A
  • protein turnover
  • dietary
  • de novo synthesis of non-essential AAs
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5
Q

What 3 things deplete supply of free amino acids?

A
  • production of protein in the body
  • synthesis of N containing compounds (ex. production of neurotransmitters)
  • degradation
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6
Q

What are the two IEM associated with deficient AA membrane transporters?

A
  • Hartnup

- Cystinuria

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7
Q

Hartnup Disease

A
  • defective transport of nonpolar or neutral AAs (LIMP GAV TTP – Leucine, Isoleucine, Methionine, Proline, Glycine, Alanine, Valine, Tryptophan, Tyrosine, Phenylalanine)
  • most commonly associated with inadequate uptake of tryptophan)
  • elevated concentration of AAs in urine
  • transporter located in kidney and small intestine
  • manifests in infancy
  • sxs: failure to thrive, nystagmus, tremor, intermittent ataxia, photosensitivity
  • hallmark sxs: photosensitivity
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8
Q

Cystinuria

A
  • defective transport of dimeric cystine and dibasic amino acids (COAL – Cystine, Ornithine, Arginine, Lysine)
  • formation of cystine crystals in kidneys
  • sxs: renal colic (intermittent abdominal pain likely due to formation of kidney stones)
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9
Q

What are the 2 ketogenic AAs?

A
  • Leucine

- Lysine

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10
Q

What molecule are the ketogenic AAs precursors to?

A

Acetyl CoA or Acetoacetate which can then be turned into alpha keto acids, ketone bodies, or FAs

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11
Q

What are the 5 ketogenic and glucogenic AAs?

A
  • Isoleucine
  • Tryptophan
  • Tyrosine
  • Threonine
  • Phenylalanine
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12
Q

What molecules are the glucogenic AAs precursors to?

A

Pyruvate or TCA intermediates (OAA, α-KG, Succinyl CoA, Fumarate) which can then be used as precursors for gluconeogenesis

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13
Q

What is the main goal of AA metabolism?

A

Sequestering N groups to excrete in urea

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14
Q

What cofactor does a transaminase rxn require?

A

Pyriodxyl-5-Phosphate (PLP

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15
Q

What is PLP a derivative of?

A

Vitamin B6

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16
Q

What cofactor does a oxidative deamination rxn require?

A

NAD+ or NADP+

derivative of Vitamin B3

17
Q

Homocysteinemia & Homocystinuria

A
  • associated with defective metabolism of homocysteine
  • result from vitamin deficiency (B6, B12, folic acid) or genetic defects in enzymes (homocysteine methyltransferase, cystathionine β-synthase)
  • Ocular sxs: lens dislocation
  • Skeletal sxs: limbs disproportionate with trunk, chest wall deformities, osteoporosis, altered facial appearance
  • CNS sxs: dementia
  • Vasculature sxs (HALLMARK SXS): stroke, thrombosis
18
Q

What cofactors does Branched-Chain α-Keto Acid Dehydrogenase require?

A
  • TPP (B1)
  • FAD (B2)
  • NAD (B3)
  • CoA (B5)
  • Lipoic Acid
19
Q

What AAs have metabolism pathways that involve the enzyme Branched-Chain α-Keto Acid Dehydrogenase?

A
  • Valine
  • Isoleucine
  • Leucine
20
Q

Maple Syrup Urine Disease

A
  • results form deficient Branched-Chain α-Keto Acid Dehydrogenase complex (BCKD) results in branched-chain α-ketoaciduria
  • branched chain AAs present in urine give it the HALLMARK maple syrup smell
  • may also accumulate in blood causing toxic effects on brain function and cognitive function
  • treatment: synthetic diet limiting BCAA (Leucine, Isoleucine, Valine)
  • prevalence higher in mennonite, amish and jewish populations
21
Q

Metabolism of what AA uses Homocysteine Methyltransferase?

A

Methionine

22
Q

Metabolism of what 2 AAs use Cystathionine Synthase?

A

Methionine and Serine

23
Q

Phenylketonuria

A
  • caused by defects in the activity of Phenylalanine Hydroxylase (PAH) (Phenylalanine -> Tyrosine)
  • involved conversion of Phe to Phenylpyruvate -> Phenyllactate and Phenylacetate
  • most common IEM
  • leads to disruptions in neurotransmission, and blocks AA transport in the brain and myelin formation, resulting in severe impairment of brain function
  • Hallmark sx: musty odor in urine
  • affected individuals often have blonde hair, blue eyes, fair skin, photosensitivity, musty body odor, neurologic disturbances
  • Treatment: dietary phenylalanine restriction, supplement with synthetic Tyr
  • clinical manifestations present before child is 2 weeks old
24
Q

What 4 molecules are derived from Tyrosine?

A
  • Melanin
  • T3 and T4
  • Dopamine
  • Norepinephrine
25
Q

Albinism

A
  • due to severe lack of melanin
  • conversion of tyrosine to melanin is blocked due to defects in enzyme Tyrosinase
  • results in partial or complete absence of pigmentation in skin, hair and eyes
26
Q

Tyrosinemias

A
  • elevated blood levels of tyrosine
  • transient tyrosinemias in newborns is attributed to delayed expression of enzymes necessary for Tyr catabolism
  • treatment: dietary restrictions of Phe and Tyr
27
Q

Tyrosinemia Type I

A
  • defect in Fumarylacetoacetate Hydrolase (fumarylacetoacetate -> fumarate)
  • results in hereditary tyrosinemia
  • formation of succinylacetone (toxic agent in liver/kidney) interferes with TCA cycle, causes renal tubule dysfunction and inhibits biosynthesis of heme
  • treatment: Nitisione (inhibitor)
28
Q

Tyrosinemia Type II

A
  • defect in Tyrosine Aminotransferase (Tyrosine -> p-Hydroxyphenlypyruvate)
  • sxs: corneal lesions (due to tyrosine deposits), intellectual disability
  • ocular manifestations include excessive tearing, redness, pain, and photophobia
29
Q

Tyrosinemia Type III

A
  • defect in 4-Hydroxyphenylpyruvate Dioxygenase (p-Hydroxyphenlypyruvate -> Homogentisate)
  • results in various neurological findings
  • very rare
30
Q

Alkaptonuria**

A
  • defect in Homogentisate Oxidase (Homogentisate -> Maleylacetoacetate)
  • inherited as autosomal recessive disease
  • also called “black urine disease” or black bone disease”
  • auto-oxidation of homogentisic acid (by light) and polymerization of products produce dark-colored pigments in urine
  • black pigmentation in intervertebral disks and ochonosis (dark sclera)
  • characteristic triad of homogentisic aciduria, ochronosis, and arthritis
31
Q

Why might excess ammonia occur?

A
  • urea cycle deficiency

- liver failure/dysfunction

32
Q

What happens in brain if you have excess ammonia?

A

leads to excess glutamine which leads to less α-KG (glutamine transformed to glutamate which is intermediate of α-KG)

33
Q

What is the rate limiting step/enzyme of urea cycle?

A

Carbamoyl Phosphate Synthetase (NH4 -> Carbamoyl P)

34
Q

What is an activator of Carbamoyl Phosphate Synthetase?

A

NAG

35
Q

What are the 2 diseases of the urea cycle?

A
  • Hyperammonemia

- Ammonia Toxicity

36
Q

Hyperammonemia

A
  • defect in any of the 6 enzymes associated with the urea cycle, or with 2 specific transporters
  • defects in mitochondrial transporters result in more severe disease
  • defects in ORNT1 typically X linked and result in excess carbamoyl P which can spill out into cytoplasm -> pyrimidine synthesis pathway, results in orotic aciduria, hyperammonemia and decreased BUN
  • treatment: limiting protein consumption, use of agents that conjugate excessive components and promote excretion
37
Q

What are the two transporters used in the urea cycle?

A
  • Citrin (shuttle Aspartate from mitochondria to cytosol)

- ORNT1 (shuttles Ornithine from cytosol to mitochondria)

38
Q

Ammonia Toxicity

A
  • excessive ammonia due to disorders in urea cycle or liver failure
  • toxic effects on brain and CNS
  • causes pH imbalance, swelling of astrocytes (= cerebral edema and intracranial hypertension)
  • TCA inhibited due to depletion of α-KG
  • depletion of glutamate disrupts NT activity (key reactant in formation of GABA)
  • can also cause mitochondrial dysfunction

SFM Exam 2 (10 decks)

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