Hemoglobin Synthesis and Porphyrias

Hemoglobin Synthesis and Porphyrias

• The presentation covered the synthesis of hemoglobin and porphyrias.
• Learning objectives included explaining the pathway of hemoglobin synthesis, listing abnormalities of hemoglobin synthesis, classifying porphyrias, and discussing porphyrias.
• Porphyrias are genetic diseases involving impaired heme synthesis.
• The presentation included examples of porphyria symptoms, such as red-brown teeth, hair growth abnormalities, skin mutilation, and disfigurement.
• Porphyrias are not a "vampire disease", despite historical misconceptions.
• King George III, the British monarch, possibly suffered from a porphyria.
• Porphyrins are cyclic compounds that usually bind iron; heme is the most common porphyrin in humans, having an iron (Fe²⁺) group.
• Hemoglobin, myoglobin, cytochromes, catalase, and NOS are proteins that contain heme as a prosthetic group.

Porphyrins

• Porphyrins are cyclic compounds consisting of four pyrrole rings linked by methenyl bridges.
• Side chains, typically acetate (A) and propionate (P), attach to the pyrrole rings, determining porphyrin type.
• Type III porphyrins are crucial for humans, while types I, II and IV are less prominent.
• Porphyrin structure and function are determined by the combination of side chains.

Heme Synthesis

• Heme is a porphyrin complex with iron at its center.
• The process takes place in the mitochondria and cytoplasm of cells, especially the liver and bone marrow.
• The initial steps leading to heme synthesis occur within the mitochondria.
• 10% of heme synthesis in the body occurs in the liver; most of the process is within the bone marrow (erythroid cells; ~85%).
• There's a series of enzymatic reactions synthesizing the porphyrin rings in distinct sites within cells.
• Steps include ALA (amino levulinic acid) synthesis, formation of porphobilinogen (PBG) and intermediates including hydroxymethylbilane (HMB).
• Then, porphyrins cycle from the mitochondria through different parts of the cell.
• These reactions involve catalysis by different enzymes.
• Heme synthesis is inhibited by heavy metals like lead.

Porphyria Classification and Case Studies

• Porphyrias can be inherited or acquired.
• Porphyria is an inherited error in metabolism that affects heme synthesis.
• The severity and manifestations of porphyrias differ depending on the specific enzyme defect and the affected tissues (e.g., liver or erythrocytes).
• Porphyrias can result in a buildup of porphyrin precursors such as porphobilinogen (PBG) and/or porphyrins in the blood, and urine.
• Porphyrias can also lead to symptoms of neuropsychiatric conditions (e.g. abdominal pain, neurological disturbances).
• A case study of a child presenting with learning difficulties and a habit of eating paint chips was given.
• A case of a 50-year-old experiencing partial complex seizures, along with skin lesions and abnormal uroporphyrin levels, was presented..

Heme Synthesis Overview

• Heme synthesis is a multi-step process that produces heme, the prosthetic group in hemoglobin and other proteins.
• The overall pathway entails the synthesis of tetrapyrroles (HMB, uroporphyrinogen I and II, coproporphyrinogen I and II, Protoporphyrin IX) through a series of enzymatic reactions.
• Steps occur in distinct cell compartments (e.g., cytoplasm and mitochondria)

Inhibition of Heme Synthesis

• Hematin inhibits ALA synthase, thus heme synthesis when globin chains are absent.
• Heavy metals inhibit various enzymes, such as ALA synthase and ferochelatases, interfering with normal heme production.
• Lead poisoning has various effects, including neurological ones, stemming from the build-up of ALA.

Porphyria Cutanea Tarda (PCT)

• PCT is the most common form of porphyria.
• Caused by a deficiency of uroporphyrinogen decarboxylase.
• Clinical onset is typically late (often in the 4th or 5th decade).
• Characterized by various symptoms, notably abnormal urine color (red-brown) reacting to UV light.
• Symptoms can be aggravated by iron overload, alcohol consumption, and hepatitis.

Erythropoietic Porphyria

• Congenital Erythropoietic Porphyria (CEP) is caused by a deficiency in uroporphyrinogen III synthase.
• Symptoms include: abnormal urine color (pink to red), photosensitivity, and accumulation of uroporphyrinogen I (and coproporphyrinogen I).
• Patients with Erythropoietic Porphyria show photosensitivity due to porphyrin accumulation.

General points relating to all porphyrias

• Porphyrias are hereditary whereas lead exposure causes an acquired porphyria.
• Porphyrias can be separated into groups, based on the location of synthesis and the types of affected enzymes.
• Different types of porphyrias affect specific steps in heme synthesis, leading to varying symptoms and accumulation patterns of various substances.
• Deficiency in any of these enzymes can interfere with the formation of porphyrins, which are intermediates on the heme synthesis pathway
• Understanding porphyrias is relevant to medicine and potentially the arts.