Heme Metabolism Notes

Heme, also known as Metalloporphyrin, consists of Porphyrin and Fe2+ (ferrous iron).

Hemeproteins contain heme as a prosthetic group.
Hemoglobin: The most abundant hemeprotein.
Myoglobin
Cytochromes: Such as Cytochrome P450, involved in detoxification in the liver.
Catalase
Peroxidases
Tryptophan pyrrolase: Breaks down tryptophan (serotonin, a neurotransmitter, is synthesized from tryptophan).
Nitric oxide synthase

Rate-limiting enzyme: ALA synthase (δ-aminolevulinate synthase) is the rate-limiting enzyme (step 1).
- ALA Synthase is inhibited by elevated levels of heme.
- Upregulated by barbiturates, steroids, alcohol, etc. (broken down by the liver by cytochrome P450).

Lead inhibits heme synthesis by binding to and inhibiting ALA dehydratase and ferrochelatase.
Mg2+ inhibits ALA dehydratase
Isoniazid (used to treat tuberculosis) decreases pyridoxine levels.

Hemin: Produced when ferrous iron ( $Fe^{2+}$ ) is oxidized to ferric iron ( $Fe^{3+}$ ). It decreases ALA synthase synthesis.
Increased cellular concentration of glucose prevents the induction of aminolevulinic acid synthase. This is the basis for administering glucose for porphyrias.
Hemin is also used to treat porphyria. Hemin inhibits the synthesis of heme by repressing ALAS1 synthesis.
Decreased iron decreases ALA synthase synthesis in bone marrow.

Low intracellular heme stimulates the synthesis of aminolevulinic acid synthase.
Low oxygen prompts the kidney to release erythropoietin, stimulating erythrocyte production and hemoglobin synthesis.

A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway.
Affected individuals accumulate heme precursors (porphyrins), which are toxic at high concentrations.

Erythropoietic porphyrias: Enzyme deficiency occurs in bone marrow.
Hepatic porphyrias: Enzyme defect occurs in the liver.
- Deficiency of uroporphyrinogen decarboxylase leads to red-brown to deep red urine.
- Deficiency of porphobilinogen deaminase leads to port wine urine.
Accumulated precursors (porphyrinogens) oxidize to form porphyrins that absorb light and get excited at 400nm, forming oxygen-free radicals that break lysosomes.
Lead can inhibit heme synthetic enzymes and cause accumulation of intermediates, leading to acquired porphyrias (avoid triggers such as sun).
Alcohol and barbiturates augment the inducibility of AL synthase, so symptoms increase.
Neuropsychiatric symptoms arise due to the accumulation of tryptophan and serotonin.