Porphyrin metabolism & porphyrias Dr. Shumaila Asim Lecture # 3

What are porphyrins ? Porphyrins are cyclic compounds that bind metal ions (usually Fe2+ or Fe3+) Porphyrin + Metal = Metalloporphyrin Most prevalent metalloporphyrin in humans is heme (metal here is iron ion) Heme consists of: One ferrous ion (Fe2+) in the centre Protoporphyrin IX (a tetrapyrrole ring) The role of heme is dictated by the enviroment created by the three dimensional structure of protein Heme is the prosthetic group of hemoglobin, myoglobin, cytochromes, catalase, tryptophan pyrrolase So, heme + globin protein = hemoglobin

Structure of porphyrins Porphyrins are cyclic molecules formed by 4 pyrrole (tetrapyrrole) rings linked by methenyl bridges. Different porphyrins vary in the nature of side chains that are attached to each of the 4 pyrrole rings. Protoporphyrin IX contains vinyl, methyl & propionate Distribution of side chains Side chains can be ordered around tetrapyrrole nucleus in 4 different ways designated I, II, III & IV series. Only type III porphyrins are physiologically important in humans Protoporphyrin IX is a member of type III series Porphyrinogens are porphyrin precursors

Structure and Properties of Iron Protoporphyrin IX propionate methyl vinyl pyrrole ring Derived from protoporphyrin IX Pattern of side chains defines isomer Binds metals: Heme- Fe2+ (ferrous) Hemin- Fe3+ (ferric) Zinc protoporphyrin (ZnPP)- Zn2+

Porphyrias Porphyria are rare inherited defects in heme synthesis. An inherited defect in an enzyme of heme synthesis results in accumulation of one or more of porphyrin precursors depending on location of block of the heme synthesis pathway. These precursors increase in blood & appear in urine of patients. Porphyria means purple colour caused by pigment-like porphyrins in urine of patients. (Diagnosed by lab investigation) Most porphyrias show a prevalent autosomal dominant pattern, except congenital eythropoietic porphyria, which is recessive

Porphyrias (cont.) Clinical manifestations of porphyrias: Generally, individuals with an enzyme defect prior to the synthesis of the tetrapyrroles manifest abdominal and neuropsychiatric signs Those with tetrapyrrole intermediates show photosensitivity with formation of reactive oxygen species (ROS) that damage membranes by oxidation resulting in the following effects: - Skin blisters, itches (pruritis) - Skin may darken, grow hair (hypertrichosis)

Porphyria Cutanea Tarda Chronic hepatic porphyria The most common type of porphyria a deficiency in uroporphyrinogen decarboxylase Clinical expression of the enzyme deficiency is influenced by various factors, such as exposure to sunlight, the presence of hepatitis B or C Clinical onset is during the fourth or fifth decade of life. Porphyrin accumulation leads to cutaneous symptoms and urine that is red to brown in natural light and pink to red in fluorescent light

Porphyrias (cont.)

Acute Hepatic Porphyrias Acute Intermittent Porphyria Porphyrias leading to accumulation of ALA and porphobilinogen cause abdominal pain and neuropsychiatric disturbances, ranging from anxiety to delirium. Symptoms of the acute hepatic porphyrias are often precipitated by administration of drugs such as barbiturates and ethanol.