Nitrogen Balance and Inborn Errors of Metabolism- Ellis

Where does most of the nitrogen in our diets come from?

proteins

What can the amino acids broken down from proteins be used for?

gluconeogenesis

ketone bodies

carbon skeletons

nitrogen containing compounds

What is nitrogen balance?

The relationship between nitrogen intake (from dietary protein) and nitrogen loss (mainly through excretion).

What characterizes nitrogen balance in a healthy adult?

Nitrogen intake equals nitrogen excretion; tissue protein remains stable.

What happens to dietary protein in nitrogen balance?

It enters the amino acid pool, supports tissue protein synthesis, other uses, or is broken down/excreted.

What happens to excess amino acids in nitrogen balance?

Their carbon skeletons may be converted to fat, while nitrogen is excreted via the urea cycle.

What is positive nitrogen balance?

When nitrogen intake exceeds nitrogen loss.

What conditions cause positive nitrogen balance?

Growth, pregnancy/lactation, and recovery from metabolic or surgical stress.

What happens to body proteins in positive nitrogen balance?

Tissue protein increases; the body builds muscle or other tissues.

What is negative nitrogen balance?

When nitrogen loss exceeds nitrogen intake.

What conditions cause negative nitrogen balance?

Inadequate protein intake, lack of essential amino acids, metabolic stress, illness, or trauma.

What happens to body proteins in negative nitrogen balance?

The body breaks down tissue proteins to supply essential amino acids; tissue protein decreases.

What is Kwashiorkor?

A form of severe malnutrition caused by inadequate protein intake, often seen in children after being weaned onto a starchy diet (e.g., yams, potatoes, banana, maize).

What happens to albumin levels in Kwashiorkor and why?

Albumin decreases because the body breaks it down to supply amino acids and maintain nitrogen balance.

Why does fatty liver occur in Kwashiorkor?

Lack of apolipoprotein B-100 prevents the liver from exporting fat (VLDL), causing fat accumulation.

What is Marasmus?

Severe malnutrition caused by overall starvation—inadequate intake of both protein and total calories.

How does subcutaneous fat differ between Kwashiorkor and Marasmus?

Kwashiorkor: Subcutaneous fat is often preserved

Marasmus: Subcutaneous fat is severely depleted

What are the ten essential amino acids?

Phenylalanine

Valine

Threonine

Tryptophan

Isoleucine

Methionine

Histidine

Arginine

Leucine

Lysine

What defines a "poor quality" dietary protein?

A protein source that is low in one or more essential amino acids (limiting amino acid).

What is a limiting amino acid?

The essential amino acid present in the lowest amount relative to the body’s needs, which limits protein synthesis.

What is the limiting amino acid in corn/maize?

lysine (very low ~4 mg/g compared to ~24 mg/g in egg protein).

Why can a diet high in corn still be protein-deficient even with adequate calories?

Corn is extremely low in lysine, so protein synthesis is limited despite adequate energy intake.

What enzyme converts phenylalanine to tyrosine?

Phenylalanine hydroxylase

What cofactor does phenylalanine hydroxylase require?

Tetrahydrobiopterin (BH₄).

What does phenylalanine hydroxylase add to phenylalanine?

A hydroxyl group (–OH) to form tyrosine.

Is BH₄ derived from a vitamin?

No. BH₄ is synthesized in the body, not vitamin-derived.

What molecule donates electrons during the phenylalanine → tyrosine reaction?

Tetrahydrobiopterin (BH₄) donates electrons and is oxidized to dihydrobiopterin (BH₂).

How is tetrahydrobiopterin (BH₄) regenerated?

By dihydrobiopterin reductase, which converts BH₂ → BH₄ using NADPH.

What amino acid is formed from phenylalanine and becomes conditionally essential if this pathway fails?

Tyrosine

Is tyrosine an essential amino acid?

No—but it becomes conditionally essential if dietary phenylalanine is inadequate.

When dietary phenylalanine is insufficient

In phenylketonuria (PKU), where the conversion of Phe → Tyr is impaired

What major products are synthesized from tyrosine?

Thyroxine (T₄) – thyroid hormone

Melanin – skin pigmentation

Catecholamines: dopamine, norepinephrine, epinephrine

What condition blocks the conversion of tyrosine to melanin?

Albinism (defective tyrosinase enzyme).

What happens to catecholamine synthesis if tyrosine is deficient?

Reduced production of dopamine, norepinephrine, and epinephrine.

What happens to thyroid hormone synthesis if tyrosine is low?

Decreased production of thyroxine (T₄).

What enzyme is deficient in classic PKU?

Phenylalanine hydroxylase.

What is the biochemical defect in PKU?

Inability to convert phenylalanine → tyrosine, causing phenylalanine accumulation.

Why is newborn screening essential for PKU?

Infants are normal at birth but develop intellectual disability if untreated; damage is irreversible once symptoms develop.

Why isn't low tyrosine the cause of intellectual disability in PKU?

Because high phenylalanine blocks Tyr/Trp from entering the brain — that transport block (not low Tyr itself) prevents neurotransmitter synthesis and causes the brain damage.

What is the dietary treatment for PKU?

Low-phenylalanine diet

Special medical foods low in protein but adequate for survival

Why can't BH₄-deficiency PKU be treated with diet alone?

Because other BH₄-dependent enzymes (tyrosine and tryptophan hydroxylases) also fail → neurotransmitter deficiencies.

Why is a tetrahydrobiopterin (BH₄) defect easier to treat than phenylalanine buildup?

Because BH₄ can be replaced directly with supplements (e.g., sapropterin), restoring enzyme function — but phenylalanine buildup cannot be “fixed”, only managed with strict lifelong diet.

What enzyme converts tyrosine to L-DOPA?

Tyrosine hydroxylase

What cofactor does tyrosine hydroxylase require?

tetrahydrobiopterin (BH₄)

What enzyme converts L-DOPA to dopamine?

DOPA decarboxylase

What cofactor does DOPA decarboxylase require?

Vitamin B₆ (PLP, pyridoxal phosphate).

What enzyme converts dopamine to norepinephrine?

Dopamine β-hydroxylase.

What cofactor does dopamine β-hydroxylase require?

Vitamin C

what enzyme converts norepinephrine to epinephrine?

Phenylethanolamine N-methyltransferase (PNMT).

What cofactor does PNMT require?

S-adenosylmethionine (SAM).

What is the order of catecholamine synthesis starting from tyrosine?

Tyrosine → L-DOPA → Dopamine → Norepinephrine → Epinephrine.

What enzyme converts tryptophan to serotonin?

Aromatic amino acid decarboxylase (after hydroxylation by tryptophan hydroxylase).

What cofactor is required for tryptophan hydroxylase?

BH₄ (tetrahydrobiopterin).

What cofactor is required for aromatic amino acid decarboxylase?

Vitamin B₆ (PLP).

What molecule is produced from serotonin before melatonin?

Acetyl-serotonin.

What cofactor converts serotonin → acetyl-serotonin?

Acetyl-CoA.

What cofactor is needed to convert acetyl-serotonin to melatonin?

SAM (S-adenosyl-methionine).

What enzyme is deficient in Tyrosinemia Type I?

Fumarylacetoacetase

→ Leads to buildup of fumarylacetoacetate & succinylacetone.

What are the key symptoms of Tyrosinemia Type I?

Liver failure, renal dysfunction, polyneuropathy, tumorigenesis, cabbage-like odor.

What enzyme is deficient in Tyrosinemia Type II?

Tyrosine aminotransferase

What are the symptoms of Tyrosinemia Type II?

Eye and skin lesions, mental retardation

What enzyme is deficient in Alcaptonuria?

Homogentisate dioxygenase.

What builds up in Alcaptonuria?

Homogentisate.

Classic finding in Alcaptonuria?

black urine

What are the three branched-chain amino acids?

Valine, isoleucine, leucine.

What is the first step in BCAA metabolism?

Transamination to form branched-chain α-ketoacids.

What enzyme performs the oxidative decarboxylation step in BCAA metabolism?

Branched-chain α-ketoacid dehydrogenase (BCKD).

Defect in BCKD leads to what disease?

Maple Syrup Urine Disease (MSUD).

What builds up in MSUD?

BCAAs and their α-ketoacids.

Which BCAA is purely ketogenic?

Leucine

What are the final metabolic products of each branched-chain amino acid?

Valine → ?

Isoleucine → ?

Leucine → ?

Valine → Succinyl-CoA (glucogenic)

Isoleucine → Acetyl-CoA + Succinyl-CoA (both)

Leucine → Acetoacetate + HMG-CoA (ketogenic)

What enzyme is deficient in Propionic Acidemia?

Propionyl-CoA carboxylase.

What cofactor does propionyl-CoA carboxylase require?

Biotin

What metabolite accumulates in Propionic Acidemia?

Propionic acid / propionyl-CoA.

What amino acids must be restricted in Propionic Acidemia?

VOMIT

Valine

Odd-chain fatty acids

Methionine

Isoleucine

Threonine

Why is glycine and ammonia elevated in someone who has propionic acidemia?

Elevated propionic acid inhibits the glycine cleavage complex (glycine build up) and carbamoyl phosphate synthetase I (ammonia build up)

What enzyme converts methionine into S-adenosylmethionine (SAM)?

Methionine adenosyltransferase.

What molecule is required to activate methionine into SAM?

ATP

Name two compounds synthesized using SAM.

Epinephrine and melatonin.

What is SAM's main function?

Major methyl donor for methylation reactions in cells.

What happens to SAM during methylation reactions?

SAM donates a methyl group to become S-adenosylhomocysteine (SAH).

What does S-adenosylhomocysteine (SAH) break down into?

Homocysteine + adenosine.

What combines to form cystathionine?

Homocysteine + serine(Enzyme: cystathionine synthase, requires PLP/B6)

What enzyme deficiency causes classic homocystinuria?

Cystathionine synthase deficiency (↓PLP activity)

What builds up in homocystinuria?

Homocysteine (and methionine ↑).

Is cysteine essential or non-essential?

Cysteine becomes essential when methionine is low (because it’s made from methionine).

What remethylates homocysteine to methionine?

Methionine synthase (B₁₂-dependent) using FH₄-CH₃ (methyl-THF) as the methyl donor.

What produces methyl-THF for the remethylation reaction?

MTHFR (methylenetetrahydrofolate reductase) converts FH₄-CH₂ → FH₄-CH₃.Requires NADPH.

What defects cause homocystinuria via the remethylation pathway?

Deficiency of:

Methionine synthase

MTHFR

→ Homocysteine ↑, methionine ↓

What is the major cause of morbidity and the most frequent cause of mortality in homocystinuria?

Thromboembolism — can involve any vessel, with increased risk in pregnancy, postpartum, and postoperative periods.

What are the main treatments for classic homocystinuria?

Limit methionine in the diet

B6 supplementation (may increase activity if enzyme has reduced B6 binding)

Goal: reduce homocysteine levels to reduce thrombosis risk

Which vitamins help lower homocysteine levels by supporting its metabolism?

Vitamin B6 (pyridoxal/PLP), folic acid (B9), and vitamin B12.