Nitrogen Metabolism Flashcards
Most common inborn error of amino acid metabolism
Phenylketonuria (PKU)
PKU cause
. Autosomal recessive Mutation in phenylalanine hydroxylase
. Catalyzes the conversion Phe to Tyr
.
What happens in PKU
. PAH enzyme defective to Phe and alternative breakdown products (phenylpyruvate, phenyllactatem phenyl acetate) accumulate
PKU symptoms and treatment
. Hypopigmentation, developmental delay, intellectual disability, and seizures
. Treatment: avoid Phe in diet but can’t be completely eliminated bc it is essential AA
Biopterin defects
. Genetic mutation in gene coding for enzymes in synthesis or recycling of BH4
. Causes impaired function of PAH and accumulation of Phe
. Same manner as PKU
Tyrosinemia of newborns
. Seen in preemies
. 4-hydroxyphenylpyruvic acid oxidase immaturity causing lack of Tyr catabolism
. Tyr and Phe accumulate in serum
. Resolves on its own after a few months
Maternal PKU syndrome
. High levels blog Phe in pregnant mom w/ PKU is toxic to fetus
. Causes microcephaly and congenital heart defects
Enzymes involved in urea cycle that if mutated will cause accumulation of ammonia and encephalopathy
. Carbamoyl phosphate synthetase I (CPSI)
. Ornithine transcarbamylase (OTC): X-linked
. Arginosuccinate synthetase (ASS)
. Arginosuccinate lyase (ASL)
. Arginase (ARG)
. All homozygous recessive except OTC
Mutations in genes for what transporters cause urea cycle disorders?
. Ornithine transporter mitochondrial 1 (ORNT1)
. Citrin (mitochondrial Asp transporter)
. N-acetylglutamate synthase (NAGS) can also cause urea cycle disorders, positive effect needed for CPS-1 activity
Lab tests for urea cycle disorders
. Blood ammonia level . Arterial blood gas . Plasma amino acid profile . Urinary orotic acid . Urinary organic acid profile . Liver function tests . Genetic testing . Biopsy for enzyme activity
Acute treatment for urea cycle disorders
. Dialysis
. ammonia/nitrogen scavengers
. Replacement therapy for deficient intermediates
. Try to get ammonia levels back to normal
Long term treatment for urea cycle disorders
. Dietary protein restriction
. Administration of N/ammonia scavengers and replacement therapy
. Liver transplants if disease is severe
Maple syrup urine disorder (MSUD)
. Mutation in gene for branched chain alpha-Keto acid dehydrogenase (BCKD)
. Enzyme catalyzes rate-limiting rxn in Leu, Iso, and Val catabolism (oxidative decarboxylation)
. AA and corresponding alpha-Keto acids build up
. Causes brain damage
. Excreting Leu smells like maple syrup
. Treatment: restricting dietary intake of BCAAs
Intermediates in branched chain amino acid catabolism
. Propionyl-CoA, isovaleryl-CoA, and methylmalonyl-CoA
. Genetic mutations in genes coding for enzymes that use these cause accumulation and development of organic acidemias
Homocystinuria
. Diseases causing accumulation of homocysteine and its excretion into urine during 1-C metabolism
. Commonly caused by mutation in cystathione beta-synthase (CBS)
. People homozygous have v high levels and develop mental retardation, thrombocytic events, osteoporosis, and lens discoloration
. B6 supplements can help, otherwise avoid dietary Met and administer betaine
Tyrosinemia type I
. Mutation in gene for fumarylacetoacetate hydrolase
. Catalyzes conversion of fumarylacetoacetate to fumarate and Acetoacetate in last step of Tyr catabolism
. Most common and most severe
. Diarrhea, vomiting, and failure to thrive from intolerance for dietary protein
. In adults accumulation of toxic compounds can cause liver cancer, liver/kidney failure
Tyrosinemia type II and III
. Caused by mutation in gene for Tyr aminotransferase and 4-hydroxyphenylpyruvate dioxygenase
Alkaptonuria
. Consequence of accumulation of homogentisic acid that is an intermediate during Tyr catabolism
. Causes homogentisic aciduria, dark urine, and arthritis
Albinism
. Type I caused by mutation in tyrosinase
. Catalyzes 1st step in conversion to Tyr to melanin in melanocytes
. Type I is most severe
Cystinuria
. Genetic defect in transporter that is unable to reabsorption filtered Cys and dibasic AA (Ornithine, Arg, Lys) in renal proximal tubule
. Causes Cys kidney stones
Hartnup disease
. Caused by defective transporter of neutral amino acids (Trp) in kidney and intestine
. Causes pellagra-like symptoms (skin rash)
Biopterin function
. Needed to provide reducing equivalents for Phe to Tys reactions
Severe neonatal onset of urea cycle disorders
. Complete absence of enzyme
. Severe hyperammonia w/in days of birth
. Poor feeding, lethargy, Tracy pea, hypothermia, irritability, vomiting, seizures, hepatomegaly, sepsis
Later-onset urea cycle disorders
. Partial deficiency of enzyme
. Mild hyperammonia: only onset w/ illness/fasting/stress because more ammonia comes in and can’t be detoxified w/ weaker enzyme function
. Nausea, vomiting, altered mental status, migraine headaches, seizures
Orotic acid
. Made from carbamoyl phosphate
. Used in pyrimidine synthesis
. High levels in urine w/ OTC deficiency
If patient has low citrulline and Ard plasma concentration, what do you suspect?
. Get urine orotic acid
. If low level then CPSI or NAGS (obtain liver biopsy)
. If high it is high get liver biopsy for OTC testing
If patient has high citrulline what do you suspect w./ urea disorder?
. ASS if no arginosuccinate (get fibroblast assay)
. If elevated arginosuccinate expect ASL and obtain RBC or fibroblast assay
What do you use for CPSI, NAGS, OTC, ASS, ASL, and ARG enzyme essays?
. CPSI, NAGS, OTC: liver biopsy
. ASS, ASL: fibroblasts
. ARG: erythrocytes
Reactions involving homocysteine
. Remethylated to Met by B12
. Can form cys through cystathionine (needs folic acid)
. Can be excreted through cystathionine form
