Nitrogen Metabolism Flashcards
IEM of amino acid transport can result in what?
Intestinal malabsorption and aberrant renal reabsorption
Where does amino acid and glucose reabsorption occur in the kidney?
Occurs in the PCT
As the filtrate passes through the PCT transport proteins from the SLC (solute carrier) gene superfamily mediate reuptake of amino acids and glucose
What is hartnup disease?
Autosomal recessive disorder caused by a defect in transporter of neutral amino acids
Affects absorption/reabsorption of neutral amino acids
Aminoaciduria: Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, Gln, Asn excreted 5-10x the normal level
Also known as pellagra-like dermatosis
Deficiency of which vitamin is also seen with Hartnup disease?
Niacin deficiency
Trp is a precursor for serotonin, melatonin and niacin (which is a precursor for NAD)
How does Hartnup disease manifest in infancy?
As failure to thrive, nystagmus (rapid and repetitive eye movement), intermittent ataxia, tremor and photosensitivity
What can trigger Hartnup disease?
Sunlight, fever, drugs or emotional or physical stress
Period of poor nutrition almost always precedes an attack
How is Hartnup disease treated?
With a repletion of niacin including a high protein diet and daily nicotinamide supplementation
Trp is an important precursor for which molecules?
Niacin (needs Vit B6)
Serotonin and melatonin
Affected in hartnup disease
What is cystinuria?
Autosomal recessive defects in the reabsorption of dimeric amino acid cystine
Also defects in reabsorption of dibasic amino acids Arg, Lys and ornithine (COAL)
Results in the formation of cystine renal calculi
What is the pt presentation for cystinuria?
Renal colic (abdominal pain that comes in waves and is linked to kidney stones)
During cystinuria, COAL is not reabsorbed and the concentration of amino acids rise where?
In the tubular lumen as the glomerular filtrate passes through the nephron
What is the main metabolic byproduct in extrahepatic tissues and the most prevalent nitrogen transporter in the blood?
Glutamine
Amino acids are converted to glutamate via what?
Transamination reactions via PLP as a cofactor
What causes classic phenylketonuria (PKU)?
Deficient/defective phenylalanine hydroxylase
What causes secondary (non-classical) PKU?
Dihydrobiopterin reductase deficiency
Deficiency of tetrahydrobiopterin (cofactor of PAH)
Defects in synthesis or regeneration of BH4
What is the most common IEM?
Phenylketonuria
What occurs with phenylketonuria?
Phe is instead converted to phenylpyruvate and then phenyllactate (causes musty odor in urine) and phenylacetate
Latter tow disrupt neurotransmission and block aa transport in teh brain as well as myelin formation resulting in severe impairment of brain function
How is PKU treated?
Dietary limit of Phe
Protein supplied with synthetic formula supplemented with Tyr
Improved metabolic control when treated with tetrahydrobiopterin (cofactor of PAH)
When the body has enough PAH this enzyme will convert Phe into what?
Tyrosine
Diagnosis and initiation of dietary treatment of classical PKU must occur when?
Before the child is 2 weeks of age in order to prevent intellectual disability
What is the role of THB (BH4)?
It is an essential cofactor in hydroxylation of aromatic aa Phe, Tyr and Trp
It is regenerated by the reduced form of NADPH dependent reduction of qBH2 catalyzed by dihydrobiopterin reductase
Defects in biosynthesis or regeneration of THB lead to secondary PKU
Production of which NTs is also disrupted with deficient THB?
Monoamine NTs such as dopamine, NE and serotonin from Tyr and Trp which leads to neurologic dysfunction
How is secondary PKU treated?
With synthetic THB
What are tyrosinemias?
Elevated blood levels of tyrosine
Transient tyrosinemia in newborns is attributed to delayed expression of enzymes necessary for Tyr catabolism
Which dietary restrictions are taken for tyrosinemias?
Restrictions of Phe and Tyr
What is tyrosinemia type I?
Defect in fumarylacetoacetate hydrolase
MC and requires a liver transplant
What are the effects of tyrosinemia type I?
Infants will have a cabbage like smell and develop severe liver failure without treatment
Formation of succinylacetone (toxic to liver and kidney) interferes with the TCA cycle causes renal tubule dysfunction and inhibits the biosynthesis of heme
What is the go to treatment for type I tyrosinemias?
Nitisinone (a 4-HPPD inhibitor)
What is type II tyrosinemia?
Attributed to defective tyrosine aminotransferase
What are the manifestations of type II tyrosinemias?
Palmar and plantar hyperkeratosis, corneal lesions (tyrosine deposition), and intellectual disability
Ocular manifestations including excessive tearing, redness, pain and photophobia
What is tyrosinemia type III?
Attributed to defective 4-HHPD and results in various neurological findings
Very rare
Confirmed by hypertyrosinema and elevated 4-hydroxyphenylpyruvate and its metabolites
What is alkaptonuria?
Due to defective homogentisate oxidase (an enzyme invovled inn the Tyr degradation pathway)
Autosomal recessive disease
“Black urine” or “black bone” disease
What does alkaptonuria cause?
Causes homogentistic acid to accumulate
Auto-oxidation of homogentistic acid (by light) and polymerization of the products produce dark colored pigments in the urine
Black pigmentation in the IV discs along with degenerative arthritis and ochonosis (dark sclera) are also observed
What is the characteristic triad of alkaptonuria?
Homogentistic aciduria, ochronosis and arthritis
What amino acid is the key nitrogen flow regulator (both a nitrogen acceptor and nitrogen donor)?
Glutamate
What is ammonia toxicity?
Excessive ammonia due to disorders in the urea cycle or liver failure can have highly toxic effects on the brain and CNS
Causes pH imbalance, swelling of astrocytes in the brain which leads to cerebal edema and intracranial HTN
Also causes mitochondrial dysfunction
What are the other effects of ammonia toxicity?
TCA cycle is inhibited due to depletion of alpha ketoglutarate (disrupts production of ATP)
Postsynaptic excitatory proteins are inhibited which depresses CNS function
Depletion of glutamate results in disruption of its NT activity (key reactant in formation of GABA)
Typically the alpha ketoglutarate to glutamate reaction doesnt occur outside the what?
Brain as glutamate dehydrogenase equilibrium favors the production fo ammonia and alpha ketoglutarate
Glutamate dehydrogenase has a very low affinity for what?
Ammonia and therefore toxic levels of ammonia would have to be present in the body for the forward reaction to process (alpha ketoglutarate and ammonia to glutamate and NADP)
In the brain the NAD/NADH ratio in mitochondria encourages what?
Oxidative deamination of glutamate to alpha ketoglutarate and ammonia
Gout is characterized as high levels of what in the blood?
Uric acid
What is primary hyeruricemia?
Overproduction of uric acid
What is secondary hyperuricemia?
Underexcretion of uric acid
What does gout result in?
Extremely painful deposits of Na irate in the joints of the extremities (gouty arthritis)
Na urate deposits in the kidneys also occur that can cause damage
What can trigger episodes of gout?
Diets rich in purines (beans, spinach and lentils) along with alcohol, meat and seafood
Acidemia stimulates reabsorption of what?
Uric acid in the kidney via urate transporter URAT1
What is used to treat gout?
Use of colchicine that decreases movement of granulocytes to affected areas
Also the use of allopurinol that inhibits xanthine oxidase and might also increase the levels of more soluble purines hypoxanthine and guanine
Altered uric acid excretion can result from what?
Decreased glomerular filtration, decreased tubular secretion or enhanced tubular reabsorption
Decreased tubular secretion occurs in pts with what?
Acidosis (e.g. DKA, ethanol or salicylate intoxication, starvation ketosis)
Organic acids that accumulate in these conditions compete with urate for secretion
What is the RLS of the urea cycle?
Conversion of NAG into carbamoyl phosphate via carbamoyl phosphate synthetase
What is the action of NAG synthase?
Produces NAG from glutamate and acetyl CoA
What is the result of the lack of NAG synthase?
Excessive accumulation of nitrogen in the form of ammonia in the blood causing hyperammonemia
Sx: vomiting, refusal to eat, progressive lethargy and coma
What is hyperammonemia?
Occurs with defects in any of the 6 enzymes associated with the urea cycle or with 2 specific transporters (which cause more severe forms)
What do defects in ornithine transcarbamoylase (X linked) cause?
Excess carbamoyl phosphate which can then spill out into the cytoplasm
Then metabolized by pyrimidine synthesis pathway to orotic acid which then accumulates and excreted in the urine —> hyperammonemia and decreased BUN
What is the treatment for hyperammonemia?
Limiting protein consumption and the use of agents that can conjugate excessive components and promote excretion
What are the 6 enzymes of the urea cycle that can cause hyperammonemia?
CPS1 Ornithine transcarbamoylase (OTC) Argininosuccinic acid synthetase (ASS1) Argininosuccinic acid lyase (ASL) Arginase (ARG1) NAGS
What two amino acid transporters are associated with hyperammonemia?
Ornithine translocase (ORNT1; ornithine/citrulline carrier) Citrin (aspartate/glutamate carrier)
Describe the role of carbamoyl phosphate synthetase II
Cytosolic enzyme
Involved in the first step of de novo pyrimidine synthesis
Doesnt require NAG like its mitochondria counterpart
Stimulated by PPPP and inhibited by UTP
Orotic acid is an intermediate in the synthesis pathway of UMP via cytosolic CPS II
A defect in UMP synthase can lead to what?
Accumulation of origin acid and result in orotic aciduria
Unlike defects in ornithine transcarbamoylase, orotic aciduria from UMP synthase deficiencies is not accompanied by hyperammonemia or reduced BUN levels
Describe CPSase I
Involved in urea cycle
Mitochondrial
NAG activated
Describe CPSase II
Involved in pyrimidine synthesis
Cytosolic
PRPP activated
What can occur in some infants that are born prematurely?
May have a developmental deficiency in UDP glucoronyl transferase
Leads to increased levels of unconjugated bilirubin coupled with high bilirubin load
What is gray baby syndrome?
Infants who develop infections are treated with an anti-microbial known as chloramphenicol
Deficiency in UDP-glucuronyl transferase causes them to be incapable of metabolizing the excessive drug load
Insufficient renal excretion of the unconjugated drug
What does gray baby syndrome lead to?
Circulatory collapse due to impaired myocardial contractility
Directly interferes with tissue respiration and oxidative phosphorylation
Conjugated (direct) bilirubin can be directly what?
Assayed whereas unconjugated (indirect) bilirubin cannot
Describe jaundice in newborns
Elevated bilirubin is normal after brith
Most newborns have jaundice
Most noticeable 2-4 days after delivery
Return to normal 7-10 days after delivery
Severe jaundice may occur if there is an increase need to replace the number of RBCs due to what?
Abnormal blood cell shapes (sickle cell anemia) Rh or type incompatibility (hemolysis) Cephalohematoma (traumatic brith) Higher levels of RBCs, small for gestational age (SGA) Infection Enzymatic deficiencies Premature birth Hemolytic anemias
Blue fluorescent light is used as a treatment for jaundice because it allows for what?
Photochemical conversion of bilirubin to water soluble isomers
Pathologic (non physiologic) jaundice can be secondary to what?
Medications, infections (rubella, syphilis, sepsis), disease that affect the liver or biliary tract (CF, hepatitis), hypoxia, many different genetic or inherited disorders and perinatal trauma
