Lecture 3: Nitrogen Metabolism Flashcards by Erik Hammond

Describe how calcium oxalate, uric acid, struvite, and cystine crystals are formed?

Calcium Oxalate: Hyperparathyroidism (Vit D, calcium, phosphate

Struvite: UTI’s (bacterial infection

Uric acid: Gout

Cystine: Cystinuria

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Who is the star of nitrogen flow in maintaining the bodies nitrogen balance?

Glutamate

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What enzymatic rxn is first step in Nitrogen removal?

Oxidative deanimation

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Which AA is the source of carbon skeleton for the Urea cycle?

Aspartate

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Rate-limiting step of the urea cycle?

Conversion of ammonia to carbamoyl phosphate via carbamoyl phosphate synthetase I and NAG activation

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What part of the kidney is responsible for nitrogen sequestration?

Proximal convoluted tubule

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Why is there a double whammy effect with IEM of AA resorption?

Affects the transporters in both the kidney and intestine causing malabsorption

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Hartnup disease is caused by an IEM affecting transporters of?

Neutral AA’s

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Cystinuria is caused by an IEM affecting transporters of?

Dibasic AA’s - COAL

Cystine, lysine, arginine, ornithine

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What is the most significant AA affected by Hartnup and why; what vitamin deficiency is commonly seen?

Tryptophan
Is a precursor for serotonin, melatonin, and niacin (NAD)
Therefore niacin deficiency is also noted

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When does Hartnup disease manifest and what are Sx’s?

Infancy as failure to thrive
Nystagmus (rapid and repetitive eye movement)
Photosensitivity
Pellagra-like dermatosis

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What triggers Hartnup and what usually precedes an attack?

Sunlight, fever, drugs, or emotional/physical stress

- Poor nutrition almost ALWAYS precedes an attack

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Best Tx for Hartnup?

Niacin repletion (Vitamin B3)

*Think about how many important rxn pathways NAD is involved in

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Cystinuria patients usually present with

Renal colic (abdominal pain linked to the kidney stones)

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Ornithine deficiency caused by cystinuria is significant why?

Ornithine is a necessary substrate for the Urea Cycle

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Classical PKU is caused by a deficiency in what enzyme needed for what rxn?

Phenylalanine hydroxylase

- Needed to convert Phe –> Tyr

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Deficiency in Tyrosinase leads to decreased production of and what clinical manifestation?

Melanin

- Albinism

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Secondary PKU is caused by deficiency in what enzyme?

Tetrahydrobiopterin (THB)

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Dx of PKU must be made before what age?

Before the child is 2 weeks of age

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Dietary Phe restriction is usually instituted if blood Phe levels are >?

> 360 µmol/dL

Some pt’s with milder forms of PKU show increased tolerance to dietary proteins and improved metabolic control when treated with what; how much?

Tetrahydrobiopterin (THB)

- 5-20 mg/kg/day

What is the common Tx for PKU

Limit dietary protein intake

- Supplement with Tyr

Elevated levels of Tyrosine is caused by?

Tyrosinemias

Tyrosinemia Type I pt’s excrete what problematic substance; what problems does it cause?

Succinylacetone
Toxic to liver and kidneys
Interferes with TCA cycle
Causes Renal Tubule dysfunction
Inhibits biosynthesis of Heme

Tyrosinemia Type II is defect in what enzyme; causes?

- Tyrosine aminotransferase | - Photophobia ad skin lesions on palms/soles

Tyrosinemia Type III defect in what enzyme; causes?

- p-hydroxyphenylpyruvate oxidase | - Intermittent ataxia

Tyrosinemia's are defects in the conversion of tyrosine to?

- Fumarate | - All defects at different steps in the pathway

What is the most common tyrosinemia and what medical intervention is typically required?

- Type I | - Liver transplant

What is the go-to Tx for Type I Tyrosinemia; prevents formation of?

- Nitisinone, a p-hydroxyphenylpyruvate oxidase inhibitor | - Prevents formation of fumarylacetoacetate

Alkaptonuria is also called what disease and is due to deficiency is what enzyme; what pathway?

- Black urine disease or black bone disease | - Homogentisate oxidase (enzyme in the Tyr degradation pathway)

What is commonly seen in the IV discs of alkaptonuria patients?

Black pigmentation in the IV discs

What is the toxic agent produced by disorders of the urea cycle; why is it so toxic?

- NH3 (ammonia) | - Non-charged so can readily diffuse through membranes of cell

Primary vs. secondary hyperuricemia

Primary: overproduction of uric acid Secondary: under-excretion of uric acid

What kind of foods need to be avoided with Gout?

Diets rich in purines (beans, spinach, lentils) along with alcohol, meat and seafood can trigger episodes

Gout is a problem that arises from the metabolism of what?

Purines!

What is the X-linked inheritance disorder (outlier) of the Urea cycle, enzyme is involved, this disorder causes what?

- Orotic aciduria - Ornithine transcarbamoylase - Causes excess carbamoyl phosphate to spill out into the cytoplasm, which is then metabolized by pyrimidine synthesis pathway to orotic acid which accumulates and is excreted in urine

Defects in what transporters result in more severe hyperammonemia; what enzyme?

- Mitochondrial transporters | - Carbamoyl phosphate synthetase I

What is carbamoyl phosphate synthetase II involved in, where is it found, stimulated/inhibited by?

- First step of de novo of pyrimidine synthesis - Cytosolic enzyme - Stimulated by PPPP, inhibited by UTP

What is the difference in orotic aciduria caused by UMP synthase deficiencies?

- Is NOT accompanied by hyperammonia or reduced BUN levels

What is carbamoyl phosphate synthetase I involved, where is it found in cell and what activates it?

- Rate-limiting step of Urea Cycle - Found in Mitochondria - Activated by NAG

What is the difference between direct and indirect bilirubin?

- Indirect is unconjugated and insoluble | - Direct is conjugated and water soluble

What is a tx for jaundice?

Blue fluorescent light allows photochemical conversion of bilirubin to water-soluble isomers

Which kind of cystals/stones must be surgically removed?

Struvite crystals

What is the glucose related kidney disease; sx's?

Fanconi-Bickel syndrome (d-Glucose) - Growth retardation, rickets, hepatorenal glycogenesis, and hypo- and hyperglycemia

What can cause severe jaundice in newborns?

- Sickle cell anemia - Rh or type incompatibility (hemolysis) - Cephalohematoma (traumatic birth) - Higher levels of RBC's as seen in small-for-gestational age (SGA) babies - Enzymatic deficiencies

Tx of Gout with Allopurinol does what?

Inhibits Xanthine Oxidase (enzyme) lowering the formation of uric acid. With an increase in excretion of hypoxanthine and xanthine. Decreasing the overall synthesis of Purines.

Gout can result from a reduction in activity of what enzyme?

Glucose 6-phosphatase

Bilirubin produced in neonatal jaundice lacks which carbohydrate?

Glucuronate - enhances the solubility of bilirubin