Heme Synthesis and Degradation

• The document discusses the synthesis and degradation of heme

Heme Synthesis Aspects

• Heme synthesis occurs in all tissues, with the highest rate in the liver and bone marrow.
• The first and last three enzymes in heme synthesis are located in the mitochondria.
• Heme is synthesized from 8 glycine and succinyl-CoA molecules.
• During synthesis, side chain modifications occur on the colorless porphyrinogens.
• The final step oxidizes porphyrinogens to porphyrin, which is colored, through methylen to methene bridges.
• Porphyrins are produced nonenzymatically from porphyrinogens in porphyrias due to light and oxidative effects.

Steps of Heme Synthesis

• There are multiple steps involved in the synthesis of heme, including several enzymes

Regulation of Heme Synthesis via ALAS1

• Heme inhibits the transcription, mitochondrial transport, and activity of ALA synthetase 1, which is the regulatory enzyme.
• ALAS1 has no iron-responsive element (IRE) in its mRNA.
• 80% of heme used in the liver is for CYP450 enzyme synthesis.
• FXR, PXR, and CAR induce the transcription of ALA synthase 1.

Erythloblasts & ALA Synthase 2

• In erythloblasts, ALA synthetase 2 expression is upregulated by both iron and heme.
• Heme induces the degradation of IRP-2 protein.
• Heme activates ALA synthase 2 translation and heme synthesis in erythloblasts.

Regulation of Globin Translation in Erythroblasts

• In GTP bound form eIF2 contributes to the initiation of globin translation
• Phosphorylation inhibits GDP/GTP exchange by its GEF.

Disorders of Heme Synthesis (Porphyrias)

• There are multiple disorders of heme synthesis
• Some porphyrias are of liver origin, some are of erythropoietic origin

Acute Intermittent Porphyria

• Acute Intermittent Porphyria is an autosomal dominant disorder
• PBG deaminase deficiency occurs on one chromosome.
• The remaining PBG deaminase activity is sufficient for erythropoiesis.
• In the liver, if heme is rapidly utilized or degraded (e.g., after taking drugs, drinking ethanol, hormonal changes that induce CYP450 enzymes), it induces ALA synthetase.
• Elevated PBG levels cannot be fully converted which results in PBG (red urine) and ALA (neurotoxicity) accumulation.
• Symptoms appear after a trigger: acute abdomen syndrome, neurological abnormalities.
• Treatment can include infusion of high concentration of heme.

Factors Triggering Heme Degradation

• Porphyrinogenic drugs/chemicals and certain conditions cause heme degradation.
• Factors that trigger heme degradation include fasting, fever, drugs such as rifampicin and barbiturates and alcohol.
• Acute porphyric attack frequency in Europe is 1:2000, with life-threatening symptoms in 1:20000.

Erythropoietic Porphyria

• Erythropoietic Porphyria is inherited recessively.
• There is a deficiency of uroporphyrinogen III cosynthetase on both chromosomes, but the enzyme activity is not lost completely
• Series I porphyrins are created instead of Series III as cosynthetase activity is low
• Coproporphyrinogen oxidase doesn't accept Coproporphyrinogen I as a substrate,
• Uroporphyrinogen I and coproporphyrinogen I accumulate and are spontaneously oxidized to porphyrins.
• Uroporphyrin I and coproporphyrin I accumulate in the bones, teeth, skin, and urine.
• Anemia, autofluorescent red blood cells and teeth, light-sensitive skin, are characteristics of erythropoietic porphyria
• Bone and teeth abnormalities develop due to low heme levels and deposition of uroporpyrin I and coproporphyrin I in the tissues.
• Erythropoietic Porphyria includes liver abnormalities and is known as Vampire disease

Vampire patient

• Drinking blood has certain benefits to the Vampire patient.

Heme degradation products

• Hemopexin-bound heme is transported to the liver to be utilized for CYP450 enzyme synthesis.
• Heme oxygenase is needed to break down heme
• Activity is dominant in the liver (heme enzymes) and RES (red blood cell degradation).
• Heme oxygenase 1 is inducible, while heme oxygenase 2 is constantly expressed.
• In macrophages, heme oxygenase 1 is an anti-inflammatory protein.
• One methene bridge is reduced to methylene.
• Heme degradation produces Bilirubin which is transported to the liver by being bound to albumin.
• Indirect bilirubin is albumin-bound; it must be separated first before determination
• Reason: haemolysis
• Direct bilirubin is bound to glucuronic acid and is water-soluble.
• Reason transport problem to the bile,. bile stone or pancreas tumor

Heme Oxygenase 2

• Heme Oxygenase 2 in the brain produces CO as a signaling molecule.
• CO, while in others NO regulate cytosolic guanylate cyclase activity in some brain area