Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Chapter III. METABOLISM OF THE MAIN CLASSES OF BIOMOLECULES

CHAPTER 18. AMINO ACID METABOLISM. II. SPECIALIZED PATHWAYS OF METABOLISM

18.4. PORPHYRIN METABOLISM

Porphyrins and their metal complexes—metalloporphyrins—serve as prosthetic groups for many Hemoproteins, which are Proteins involved in oxidation-reduction reactions in animal and plant Cells. Examples of hemoproteins containing metalloporphyrin groups include Fe²⁺-containing Hemoglobin (an O₂-transport protein of erythrocytes) and Myoglobin (an O₂-storage protein of Muscles), (Fe²⁺-Fe³⁺)- and (Cu¹⁺-Cu²⁺)-containing Cytochromes, (Fe²⁺-Fe³⁺)-containing Enzymes such as catalase, peroxidases, Tryptophan pyrrolase, and the Mg²⁺-containing plant pigment chlorophyll.

Structure of Porphyrins

Porphyrins are cyclic compounds whose core structure is based on the aromatic heterocyclic system known as porphin. Porphin, in turn, is a tetrapyrrole formed by the linkage of four pyrrole nitrogen heterocycles via methenyl bridges (-CH=).

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Structure of pyrrole and porphin.

Porphyrins are derivatives of porphin with substitutions at positions 1, 2, 3, 4, 5, 6, 7, and 8.

Naturally occurring porphyrins, which form metal complexes that are part of many physiologically important hemoproteins, are compounds in which the eight hydrogen atoms of the porphyrin core are replaced by various hydrocarbon radicals. Depending on The structure of their side chains, porphyrins are classified into several groups: uroporphyrins, coproporphyrins, protoporphyrins, etioporphyrins, hematoporphyrins, mesoporphyrins, and deuteroporphyrins. Each class of porphyrins includes several isomers, which are designated by letters of the Latin alphabet.

The metabolic precursors of porphyrins are called porphyrinogens (such as uroporphyrinogens, coproporphyrinogens, etc.). Unlike porphyrins, porphyrinogens lack conjugated methenyl structures (in their molecules, the pyrrole rings are connected by saturated methylene (-CH₂-) bridges); they are colorless compounds that convert into colored porphyrins upon enzymatic or non-enzymatic oxidation (induced by atmospheric oxygen).

The heme moiety of oxygen-binding proteins in The Human Body—such as hemoglobin, myoglobin, and cytochromes of the respiratory chains—contains a porphyrin designated as protoporphyrin III (according to Fisher's older nomenclature, this porphyrin was classified as protoporphyrin IX, a designation still widely used today).

Synthesis of Porphyrins

The Biosynthesis of porphyrins is closely linked to Amino acid METABOLISM: the precursors for The formation of the pyrrole rings of porphyrins are Glycine and succinyl-CoA. The sequence of synthetic reactions is as follows:

1. Interaction of glycine with succinyl-CoA to form α-amino-β-ketoadipic acid:

2. Decarboxylation of α-amino-β-ketoadipic acid to form δ-aminolevulinic acid (ALA):

Both of these reactions leading to the formation of ALA are catalyzed by the enzyme δ-aminolevulinate synthase (ALA synthase). ALA synthase is a PLP-dependent enzyme localized in the Cell/35.html">Mitochondria and Endoplasmic reticulum, with the highest concentrations found in Liver cells (where it participates in the Synthesis of the prosthetic groups of mitochondrial cytochromes and microsomal cytochrome P450), Bone Marrow cells, and immature erythrocytes (reticulocytes).

3. Condensation of two molecules of δ-aminolevulinate via dehydration to form a cyclic structure—porphobilinogen—the direct metabolic precursor of porphyrins:

Upon losing its amino group, δ-aminolevulinate can also be converted into substrates of The Citric Acid Cycle—α-ketoglutarate and subsequently succinyl-CoA—allowing The process of porphobilinogen synthesis to be represented as a metabolic cycle known as the Shemin-Rittenberg cycle (D. Shemin, D. Rittenberg, 1944):

4. Synthesis of tetrapyrrole structures.

The condensation of four porphobilinogen units leads to the formation of various types of porphyrins. When the pathway is directed toward the synthesis of heme — the prosthetic group of hemoglobin and certain cytochromes — the Generation of the heme porphyrin ring, protoporphyrin IX, proceeds via the following sequence of reactions:

4.1. Synthesis of uroporphyrinogen III from four molecules of porphobilinogen:

The reaction involves two proteins:

- the enzyme uroporphyrinogen synthase (porphobilinogen deaminase);

- the protein uroporphyrinogen III cosynthase.

The catalytic action of uroporphyrinogen synthase alone, in the absence of the cosynthase, leads to the formation of a non-physiological isomeric porphyrin, uroporphyrinogen I (such a situation may occur in one of the forms of Inherited Disorders of porphyrin synthesis). The presence of the cosynthase directs the condensation of porphobilinogen molecules specifically toward the formation of uroporphyrinogen III.

UPG synthase — uroporphyrinogen synthase; A — acetate (-CH₂COOH); P — propionate (-CH₂CH₂COOH)

Uroporphyrinogen III also serves as a metabolic precursor in the synthesis of vitamin B₁₂ by Bacteria, and chlorophyll by plants and bacteria.

4.2. Conversion of uroporphyrinogen III to coproporphyrinogen III. The Mechanism of this reaction involves the decarboxylation of side-chain acetate groups (catalyzed by the enzyme uroporphyrinogen decarboxylase).

4.3. Conversion of coproporphyrinogen III to protoporphyrinogen III and protoporphyrin III (IX). The process involves The oxidative decarboxylation of side chains and The oxidation of methylene bridges, and is catalyzed by specific mitochondrial oxidases — coproporphyrinogen oxidase and protoporphyrinogen oxidase, respectively.

The insertion of a ferrous iron atom into the protoporphyrin IX molecule, catalyzed by the mitochondrial enzyme ferrochelatase (heme synthase), completes the synthesis of heme (protoheme IX). The conjugation of heme with the globin protein results in the formation of hemoglobin.

The reactions converting uroporphyrinogen III to the protoporphyrin IX molecule and the synthesis of heme are illustrated in the scheme below:

The source of iron ions for heme is the iron-storage tissue protein ferritin, a single molecule of which can bind 4,500 Fe³⁺ ions. In turn, ferritin receives iron from the protein transferrin, which transports iron in Blood Plasma derived from The breakdown of erythrocyte hemoglobin and the intestinal absorption of iron ions.

The overall sequence of reactions for heme synthesis from glycine and succinyl-CoA is shown in the scheme:

The regulation of porphyrin synthesis occurs at the level of ALAS (ALA synthase) via a negative feedback mechanism, such that the accumulation of heme inhibits its own biosynthesis. The end product of the biosynthetic pathway — heme — acts as a corepressor that, together with an aporepressor protein, forms a negative modulator that counteracts the Translation of ALA synthase mRNA on Ribosomes, thereby blocking the synthesis of the enzyme.

Inherited Disorders of Porphyrin Metabolism

Inherited disorders of porphyrin biosynthesis (Porphyrias) are metabolic defects (enzymopathies) in which porphyrins and their precursors accumulate in excessive amounts in human Tissues, particularly in the Skin and subcutaneous tissue, and are excreted in urine and feces.

There are several most common clinical and biochemical types of porphyrias, which differ in the defective Gene involved and the clinical manifestation of the enzymopathy. Porphyrias have been described that develop As a result of defects in almost every enzyme of the heme synthesis pathway. Porphyrias are inherited as autosomal recessive or autosomal dominant diseases.

The MAIN CLINICAL MANIFESTATIONS of porphyrias are photosensitivity and neurological disorders.

Photosensitivity

The abnormal deposition of porphyrins with various molecular structures in the skin leads to its photosensitivity and The Development of photodermatitis. The Molecular Basis of these pathological manifestations is the generation, under The Influence of sunlight with a wavelength of about 400 nm, of reactive oxygen species such as singlet oxygen ¹O₂ and porphyrin peroxide radicals such as RO₂, which damage cell membranes and lead to cell death.

Neurological disorders

Neurological manifestations in porphyrias present with pathological symptoms affecting both the Peripheral Nervous system (such as dysesthesia, impaired bowel motility, neuromuscular transmission defects, and respiratory Muscle paralysis) and the Central Nervous System.

Depending on the primary site of the specific enzymatic defect, porphyrias are classified into erythropoietic and hepatic forms.

Erythropoietic porphyria (Gunther's disease) is a pathology caused by a deficiency in uroporphyrinogen III cosynthase. This biochemical defect leads to the formation of a non-physiological uroporphyrinogen isomer—uroporphyrinogen I. The disease is characterized by reddish discoloration of the urine (and occasionally bones and Teeth), resulting from the renal accumulation of uroporphyrinogen I, which is converted into uroporphyrin I in the urine.

Hepatic porphyrias. There are several types of hepatic porphyrias, characteristically marked by neurological disorders associated with the excessive accumulation of serotonin in the body due to reduced synthesis of the heme-containing enzyme tryptophan pyrrolase.

The most common Clinical forms of hepatic porphyrias include:

- acute intermittent porphyria (pyrroloporphyria), a disorder caused by a deficiency of the enzyme uroporphyrinogen synthase (porphobilinogen deaminase);

- hereditary coproporphyria, an enzymopathy caused by a deficiency of the enzyme coproporphyrinogen oxidase.