Conversion of Amino Acids to Specialized Products

Biochemistry

2nd stage
Dr.Lamees Majid Al-Janabi

Conversion of amino acids to specialized products

Porphyrin Metabolism

Porphyrins are cyclic compounds that readily bind metal ions—usually Fe2+ or Fe3+. The most prevalent metalloporphyrin in humans is heme, which consists of one ferrous (Fe2+) iron ion coordinated in the center of the tetrapyrrole ring of protoporphyrin IX .
Heme is the prosthetic group for hemoglobin, myoglobin, the cytochromes, catalase, and tryptophan pyrrolase. These hemeproteins are rapidly synthesized and degraded. For example, 6 to 7 g of hemoglobin are synthesized each day to replace heme lost through the normal turnover of erythrocytes. Coordinated with the turnover of hemeproteins is the simultaneous synthesis and degradation of the associated porphyrins, and recycling of the bound iron ions.

Structure of porphyrins

Porphyrins are cyclic molecules formed by the linkage of four pyrrole rings through methenyl bridges.

Biosynthesis of heme

The major sites of heme biosynthesis are the liver, which synthesizes a number of heme proteins (particularly cytochrome P450), and the erythrocyte-producing cells of the bone marrow, which are active in hemoglobin synthesis. In the liver, the rate of heme synthesis is highly variable, responding to alterations in the cellular heme pool caused by fluctuating demands for heme proteins.
In contrast, heme synthesis in erythroid cells is relatively constant, and is matched to the rate of globin synthesis. The initial reaction and the last three steps in the formation of porphyrins occur in mitochondria, whereas the intermediate steps of the biosynthetic pathway occur in the cytosol .

[Note: Mature red blood cells lack mitochondria and are unable to synthesize heme.]

End-product inhibition by hemin: When porphyrin production exceeds the availability of globin (or other apoproteins), heme accumulates and is converted to hemin by the oxidation of Fe2+ to Fe3+.
Hemin decreases the activity of hepatic ALA synthase by causing decreased synthesis of the enzyme, through inhibition of mRNA synthesis and use (heme decreases stability of the mRNA).
[Note: In erythroid cells, heme synthesis is under the control of erythropoietin and the availability of intracellular iron.]

Porphyrias

Porphyrias are rare, inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors .
Each porphyria results in the accumulation of a unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic pathway.
[Note: “Porphyria” refers to the purple color caused by pigment-like porphyrins in the urine of some patients with defects in heme synthesis.]


Clinical manifestations:
The porphyrias are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in the erythropoietic cells of the bone marrow or in the liver. Hepatic porphyrias can be further classified as acute or chronic. Individuals with an enzyme defect leading to the accumulation of tetrapyrrole intermediates show photosensitivity—that is, their skin itches and burns (pruritis) when exposed to visible light.

Chronic porphyria: Porphyria cutanea tarda, the most common porphyria, is a chronic disease of the liver and erythroid tissues. The disease is associated with a deficiency in uroporphyrinogen decarboxylase, but clinical expression of the enzyme deficiency is influenced by various factors, such as hepatic iron overload, exposure to sunlight, and the presence of hepatitis B or C, or HIV infections. Clinical onset is typically 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.




Urine from a patient with porphyria cutanea tarda (right) and from a patient with normal porphyrin excretion (left).

Acute hepatic porphyrias: Acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria) are characterized by acute attacks of gastrointestinal, neurologic/psychiatric, and cardiovascular symptoms. Porphyrias leading to accumulation of ALA and porphobilinogen, such as acute intermittent porphyria, cause abdominal pain and neuropsychiatric disturbances. Symptoms of the acute hepatic porphyrias are often precipitated by administration of drugs such as barbiturates and ethanol, which induce the synthesis of the heme-containing cytochrome P450 microsomal drug oxidation system.

Erythropoietic porphyrias: The erythropoietic porphyrias (congenital erythropoietic porphyria and erythropoietic protoporphyria) are characterized by skin rashes and blisters that appear in early childhood. The diseases are complicated by cholestatic liver cirrhosis and progressive hepatic failure.