Dai2-AAcatabolism

Question 1

What is the general treatment regimen for urea cycle disorders?

Answer 1

• Reduce nitrogen intake
• Increase alternative N excretion (Benzoate/ phenylacetate supplementation to excrete N as hippurate)
• Stimulate residual urea cycle activity (Arginine supplementation)

Question 2

How does Arginine supplementation work?

Answer 2

-provides substrate/positive regulator to facilitate the remaining urea cycle machinery (e.g., stimulates CPSI and overall pathway activity via N-acetylglu; enhances excretion of citrulline or argininosuccinate; stimulate protein synthesis)

Question 3

How is ammonia (N) produced in extraheptic tissues transported into the bloodstream and liver, the site of glu oxidative deamination and urea cycle?

Answer 3

1) In the form of glutamine (from glutamate and ammonia, by glutamine synthetase)
2) Transport of N from muscle to liver in the form of alanine (also carries pyruvate from muscle to liver for glucose production)

Question 4

What is the fate of carbon skeleton?

Answer 4

α-ketoglutarate, pyruvate, oxaloacetate, fumarate,succinyl CoA, acetyl CoA, acetoacetylCoA

• used for gluconeogenesis
• used for synthesizing fatty acids & ketone bodies
• metabolized to CO2 & water, & generate energy

Question 5

What are glucogenic Amino aids?

Answer 5

Glucogenic amino acids: give rise to a net production of pyruvate or TCA cycle intermediates, all of which are precursors to glucose via gluconeogenesis

Question 6

What are kerogen in Amino aids?

Answer 6

• Those that give rise to acetyl-CoA or acetoacetyl CoA, which can be converted to acetoacetate (one of the ketone bodies)
• Leucine and lysine

Question 7

What is Nonketotic Hyperglycinemia (Glycine Encephalopathy)?

Answer 7

• Defect in the glycine cleavage complex (this converts glycine to CO2 and ammonia)
• increased level of glycine in blood
• severe mental retardation, seizures and death
• Glycine is an inhibitory neurotransmitter, acting on the spinal cord and brain stem

Question 8

How is used asparaginase used in cancer therapy?

Answer 8

• Normal cells can synthesize asparagine (Asn), but leukemic cells cannot make enough, so they rely on blood Asn
• Administration of asparaginase eliminates blood-borne Asn, leaving cancer cells w/o source of Asn

Asn—asparaginase–>Asp—> oxaloacetate

Question 9

What is histidinemia?

Answer 9

• Deficiency in histidase, so high histidine levels in blood and urine
• Asymptomatic or later hyperactivity, speech impediment, developmental delay, learning difficulties, & mental retardation

His—histidase—>urocanic acid–> FIGlu–THF–> α-ketoglutarate

Question 10

What is the Figlu test?

Answer 10

• Test of vitamin b12 deficiency, folic acid deficiency, liver disease, or genetic deficiency of glutamate formiminotransferase, based on urinary excretion of figlu, an intermediate metabolite in histidine catabolism
• If enough THF after His administration, there should not be FIGlu accumulated

Question 11

What is the catabolic pathway of branched amino acids?

Answer 11

• Val, Ile, Leu
• Transamination by hBCAT –> branched chain a-keto acids
• Oxidative decarboxylation by branched chain a-keto acid dehydrogenase –> intermediates–> AcetylCoA or SuccinylCoA

Question 12

What is maple syrup urine disease?

Answer 12

• Defective or missing branched-chain α-keto acid dehydrogenase BCKD
• Elevated levels of branched-chain amino acids and their α-keto acids in blood and urine
• Urine of patients has the odor of maple syrup
• Mental and physical retardation, abnormal muscle tone, ketosis, coma, short life span
• Rare, autosomal recessive 1/200,000
• Treatment: diet low in branched-chain aa
• Some of the patients respond to therapeutic doses of thiamine, the cofactor

Question 13

What is tyrosinemia?

Answer 13

• Tyrosinemia II: shows skin and eye defects, mental retardation, accumulation of tyrosine because of defect in tyrosine aminotransferase
• Tyrosinemia I: liver & renal disease, polyneuropathy, caused by defect in last step of Phe catabolism.

Question 14

What is Alkaptonuria?

Answer 14

• Absence of homogentisate oxidase
• Accumulation of homogentisate in urine converts it to dark substance
• Rare and relatively benign, but at old ages, deposition of oxidation products of homogentisate in cartilage tissues -> arthritis, ochronosis
• Low Phe/Tyr diet and alleviating symptoms

Question 15

What causes albinism?

Answer 15

• defects in tyrosine metabolism leading to deficient melanin production
• e.g., mutations in tyrosinase, which catalyzes rate limiting step of melanin production
• low level or absence of pigment
• Pku patients – light pigment bc accumulated compounds interfere with tyrosinase activity

Question 16

What is Phenylketonuria (PKU)?

Answer 16

• defect in Phe to Tyr conversion
• Catalyzed by phenylalanine hydroxylase
• Requires molecular oxygen
• Requires tetrahydrobiopterin (BH4) as a cofactor
• One of the most common inborn errors of amino acid metabolism

Question 17

What are the classical and non classical PKUs?

Answer 17

-Classical PKU: deficiency or absence of
phenylalanine hydroxylase
-Non-classical PKU: defect in tetrahydrobiopterin
(BH4) cofactor synthesis
-Phe as well as phenylketones (phenylpyruvate, phenylacetate, phenyllactate) accumulate

Question 18

What is the phenotype of PKU

Answer 18

Untreated phenotype
• Mental retardation, seizures, tremor, rashes, hyperactivity, failure to growth, talk, or walk, hypopigmentation
• Neurological/behavioral disorders

Neonatal disease
• NO PHENOTYPE - only detected by screen
• Risk of profound mental retardation - IQ 10-30
• Irreversible damage to myelination

Question 19

What is The Guthrie test?

Answer 19

Bacterialculture testthatdetectselevatedPhelevelsinbloodsamplesfromnewbornbabies

Question 20

What is the diet of PKU patients?

Answer 20

Individuals with PKU are treated with a special diet low in phenylalanine

• Tyr becomes essential
• Avoid aspartame bc phe is one of its degradation products

Question 21

What is maternal PKU?

Answer 21

• High blood Phe in mother has teratogenic effect on a NORMAL fetus
– defective embryonic development, risk for:
– Mental retardation
– Microcephaly
– Cardiac defects
– Intrauterine growth retardation
– Low birth weight

Question 22

Why does Phe restriction does not eliminate problems arising from BH4 deficiency in atypical PKU?

Answer 22

• Because it is ALSO required for the synthesis of several neurotransmitters like Dopamine
• Guanine nucleotide metabolic defects – reduced BH4 – reduced neurotransmitters (Lesch Nylan disease)

Question 23

What is Homocystinuria?

Answer 23

• Defect in transsulfuration pathway (cystathionine synthase deficiency or reduced affinity to B6 cofactor)
• Defect in remethylation pathway (methionine synthase deficiency)
• Accumulation of homocysteine & methionine in blood and urine
• Neurotube defect, mental retardation, vascular disorders, heart defect, dislocation of the lens, osteoporosis, long limbs (like Marfan S.)
• Treatment: restrict met, + VitB6, B12, & folate

Question 24

What is Marfan syndrome?

Answer 24

-Disorder of connective tissue: affects skeletal system, cardiovascular system, eyes, & skin

Question 25

What are the two pathways methionine can go through?

Answer 25

1) Transulfuration: at homocysteine step, it goes on to become cysteine. Cystathionine synthase, B6 is a cofactor.
2) Remethylation: at homocysteine step, it goes on to reform methionine and THF. Methionine synthase, B12 is a cofactor.