Dai2-AAcatabolism Flashcards
What is the general treatment regimen for urea cycle disorders?
- Reduce nitrogen intake
- Increase alternative N excretion (Benzoate/ phenylacetate supplementation to excrete N as hippurate)
- Stimulate residual urea cycle activity (Arginine supplementation)
How does Arginine supplementation work?
-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)
How is ammonia (N) produced in extraheptic tissues transported into the bloodstream and liver, the site of glu oxidative deamination and urea cycle?
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)
What is the fate of carbon skeleton?
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
What are glucogenic Amino aids?
Glucogenic amino acids: give rise to a net production of pyruvate or TCA cycle intermediates, all of which are precursors to glucose via gluconeogenesis
What are kerogen in Amino aids?
- Those that give rise to acetyl-CoA or acetoacetyl CoA, which can be converted to acetoacetate (one of the ketone bodies)
- Leucine and lysine
What is Nonketotic Hyperglycinemia (Glycine Encephalopathy)?
- 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
How is used asparaginase used in cancer therapy?
- 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
What is histidinemia?
- 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
What is the Figlu test?
- 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
What is the catabolic pathway of branched amino acids?
- Val, Ile, Leu
- Transamination by hBCAT –> branched chain a-keto acids
- Oxidative decarboxylation by branched chain a-keto acid dehydrogenase –> intermediates–> AcetylCoA or SuccinylCoA
What is maple syrup urine disease?
- 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
What is tyrosinemia?
- 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.
What is Alkaptonuria?
- 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
What causes albinism?
- 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
What is Phenylketonuria (PKU)?
- 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
What are the classical and non classical PKUs?
-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
What is the phenotype of PKU
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
What is The Guthrie test?
Bacterialculture testthatdetectselevatedPhelevelsinbloodsamplesfromnewbornbabies
What is the diet of PKU patients?
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
What is maternal PKU?
• 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
Why does Phe restriction does not eliminate problems arising from BH4 deficiency in atypical PKU?
- Because it is ALSO required for the synthesis of several neurotransmitters like Dopamine
- Guanine nucleotide metabolic defects – reduced BH4 – reduced neurotransmitters (Lesch Nylan disease)
What is Homocystinuria?
- 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
What is Marfan syndrome?
-Disorder of connective tissue: affects skeletal system, cardiovascular system, eyes, & skin
