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porphyrins

Wednesday 30 July 2008

Definition: A porphyrin is a heterocyclic macrocycle derived from four pyrroline subunits interconnected via their α carbon atoms via methine bridges (=CH-).

Porphyrins are aromatic and they obey Hückel’s rule for aromaticity in that they possess 4n+2 pi electrons which are delocalized over the macrocycle.

The macrocycle, therefore, is a highly-conjugated system, and, as a consequence, is deeply coloured - the name porphyrin comes from a Greek word for purple. The macrocycle has 22 pi electrons.

The parent porphyrin is porphine, and substituted porphines are called porphyrins. Many porphyrins occur in nature, such as in green leaves and red blood cells, and in bio-inspired synthetic catalysts and devices.

Metals

Porphyrins bind metals to form complexes. The metal ion, usually with a charge of 2+ or 3+, is in the central N4 cavity formed by the loss of two protons. Most metals can be inserted. A schematic equation for these syntheses is shown:

H2porphyrin + [MLn]2+ → M(porphyrinate)Ln-4 + 4 L + 2 H+

A porphyrin in which no metal is inserted in its cavity is sometimes called a free base.

Heme

Some iron-containing porphyrins are called hemes; and heme-containing proteins, or hemoproteins, are found extensively in nature. Hemoglobin and myoglobin are two O2-binding hemoproteins that contain iron porphyrins.

Porphyrin biosynthesis

The "committed step" for porphyrin biosynthesis is the formation of D-aminolevulinic acid (dALA) by the reaction of the amino acid glycine and succinyl-CoA, from the citric acid cycle.

Two molecules of dALA combine to give porphobilinogen (PBG), which contains a pyrrole ring.

Four PBGs are then combined through deamination into hydroxymethyl bilane (HMB), which is hydrolysed to form the circular tetrapyrrole uroporphyrinogen III.

This molecule undergoes a number of further modifications. Intermediates are used in different species to form particular substances, but, in humans, the main end-product protoporphyrin IX is combined with iron to form heme. Bile pigments are the breakdown products of heme.

Pathology: porphyrias

The anomalies of heme biosynthesis are porphyrias.

Enzyme Substrate Product Chromosome EC OMIM Porphyria
ALA synthase Glycine, succinyl CoA D-Aminolevulinic acid 3p21.1 2.3.1.37 MIM.125290 none
ALA dehydratase D-Aminolevulinic acid Porphobilinogen 9q34 4.2.1.24 MIM.125270 ALA-Dehydratase deficiency
PBG deaminase Porphobilinogen Hydroxymethyl bilane 11q23.3 2.5.1.61 MIM.176000 acute intermittent porphyria
Uroporphyrinogen III synthase Hydroxymethyl bilane Uroporphyrinogen III 10q25.2-q26.3 4.2.1.75 MIM.606938 congenital erythropoietic porphyria
Uroporphyrinogen III decarboxylase Uroporphyrinogen III Coproporphyrinogen III 1q34 4.1.1.37 MIM.176100 porphyria cutanea tarda
Coproporphyrinogen III oxidase Coproporphyrinogen III Protoporphyrinogen IX 3q12 1.3.3.3 MIM.121300 coproporphyria
Protoporphyrinogen oxidase Protoporphyrinogen IX Protoporphyrin IX 1q22 1.3.3.4 MIM.600923 variegate porphyria
Ferrochelatase Protoporphyrin IX Heme 18q21.3 4.99.1.1 MIM.177000 erythropoietic protoporphyria