Protoporphyrin side chains

Esterification of the propionic acid side chain at C-13 (ring C) with a methyl group catalyzed by S-adenosyl-L-methionine-magnesium protoporphyrin 0-meth-yltransferase yields protoporphyrin IX monomethyl ester (MPE), which originates protochlorophyllide by a P-oxidation and cyclization of the methylated propionic side chain. This molecule contains a fifth isocyclic ring (ring E), the cyclopentanone ring that characterizes aU chlorophylls. 

Figure 7.2 (a) Schematic representation of the structure of B. subtilis ferrochelatase. Domain I is coloured green and domain II blue. The parts of the chain in red build up the walls of the cleft, and the region in yellow makes the connection between the domains. The N- and C-termini are marked, (b) The proposed active site of ferrochelatase with protoporphyrin IX molecule (red) modelled into the site. The backbone atoms of the protein are in purple, the side-chains in blue. Reprinted from Al-Karadaghi et ah, 1997. Copyright (1997), with permission from Elsevier Science. 

HRP C contains two different types of metal center (i.e., iron(III) protoporphyrin IX-heme group and two calcium atoms) that are fundamental for the integrity of the enzyme. The heme group is attached to the enzyme at His 170 by a coordinate bond between the histidine side-chain NE2 atom and the heme iron atom. The second axial coordination site is unoccupied in the resting state of the enzyme but available to hydrogen peroxide during enzyme turnover. Small molecules such as carbon monoxide, cyanide, fluoride, and azide bind to the heme iron atom at this distal site, giving six-coordinated PX complexes. 

Metal ion chelates of various porphyrins, differing in their substituents at positions 1-8, are intimately involved in a great number of life processes. Iron protoporphyrin (13) is the most common form and serves as the cofactor of a large number of enzymes. Usually (13) is non-covalently bound to its conjugate apoenzymes. Examples of covalently attached (13) are provided by c-type cytochromes, the attachment being between two vinyl side chains of (13) and two cysteine residues of the protein. Other biologically important derivatives of porphyrin include chlorophyll a (14), bacteriochlorophyll a and heme a (B-79MI11002). 

This reaction does not occur readily spontaneously but is catalyzed by an ATP-dependent magnesium protoporphyrin chelatase.419 422 Subsequently, the carboxyethyl side chain on ring C undergoes meth-ylation (Fig. 24-23, step b) and (3 oxidation (step c). 

The porphyrin of heme is known as protoporphyrin IX, and the associated metal is iron [as Fe(II) or Fe(III)]. You will notice that the porphyrin ring carries methyl, ethenyl, and propanoic acid side chains ... 

Iron protoporphyrin IX (heme) is found in the b-type cytochromes and in hemoglobin and myoglobin. In heme c, cysteine residues of the protein (R) are attached covalently by thioether links to the two vinyl (—CH=CH2) groups of protoporphyrin IX. Heme c is found in the c cytochromes. In heme A, which is found in the a cytochromes, a 15-carbon isoprenoid side chain is attached to one of the vinyls, and a formyl group replaces one of the methyls. 

Because of their structural and spectroscopic analogies with the hemo-chromes Fe(P)L2, e.g. the protoporphyrin derivative 3 (L, L = Py or 1-Meim), the corresponding 4d and 5d homologs are named ruthenochromes or osmo-chromes . The hemochromes derive their name from the cytochromes, the widespread electron-carrying heme proteins. Cytochrome b (coordination type F, M = Fe) has two imidazole donors from histidine side chains at the central iron, cytochrome c (coordination type G, M = Fe) an imidazole and a methyl-thioether function from a methionine. F is an axially symmetrical, G an axially unsymmetrical system. 

Note that uroporphyrinogen III is not a symmetrical molecule. During its synthesis, one of the pyrrole rings (ring D) is reversed, with the result that the acetate and propionate side chains are not symmetrically arranged around the porphyrin ring. The key porphyrin intermediate in cytochrome and hemoglobin synthesis is protoporphyrin IX (Fig. 15-21). 

In many of the haemoproteins we shall be discussing, the protoporphyrin IX group is held to the polypeptide chain only by hydrogen bonding, Van der Wools forces and iron-protein bonds. In several other cases, notably in cytochrome-c and its related compounds, the haem is covalently linked to the protein via substituents at the pyrrole carbon atoms. Cyto-chrome-c can be regarded as an iron protoporphyrin IX group with the addition of a protein cysteine side-chain across the vinyl double bonds giving two thio-ether links (Fig. 3). 

Most known multiheme cytochromes and enzymes belong to the family of cytochromes c (see Iron Heme Proteins Electron Transport), which contain Fe-protoporphyrin IX covalently attached to the polypeptide chain by two thioether bonds, formed by addition of two cysteinyl residues to the vinyl side-chains of the porphyrin ring. The two cysteines form a characteristic amino acid sequence motif CXXCH, usually indicative of heme c ligation, and where the histidine is the axial fifth ligand to the iron. For some cytochromes (see Section 2), the number of residues between the two cysteines can be three or four. The heme redox potentials in cytochromes c cover a wide range and are tuned by several factors, usually dominated by the type of axial ligation and the extent of solvent exposure of the heme. ... 

FIGURE 17.23. (a) Chemical formula of camphor, drawn in various orientations, (b) Chemical formula of protoporphyrin IX. The upper axial ligand is dioxygen (O2) and the lower axial ligand is a thiolate (S ) side chain on the enzyme (Cys 357). 

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