Chemistry and biology of heme. Effect of metal salts, organometals, and metalloporphyrins on heme synthesis and catabolism, with special reference to clinical implications and interactions with cytochrome P-450.
Although free porphyrins occur in nature in small quantities, no known function has been assigned to them. In contrast, heme and cobalamin, which are Fe and Co chelates of porphyrins or porphyrin derivatives, respectively, carry out crucial biological functions. Heme is the prosthetic group for a number of hemoproteins. These include myoglobin and hemoglobin, which carry out oxygen binding or transport; mitochondrial cytochromes aa3, b, c, and c3, which are important in transferring electrons; microsomal cytochrome P-450, which catalyzes mixed-function oxidations; catalase, which decomposes H2O2; peroxidase, which activates H2O2; and tryptophan pyrrolase, which catalyzes the oxidation of tryptophan. Recently, heme has also been shown to be the prosthetic group of prostaglandin and peroxide synthetase and indoleamine dioxygenase. The elegant studies of the biochemical pathway for the formation of heme demonstrated the arrangement in the porphyrin macrocycle of the carbon and nitrogen atoms originating from the eight glycine and the succinic acid molecule that are the precursors of porphyrins. There are eight enzymes involved in the synthesis of heme. The first and last three of these enzymes are localized in mitochondria, while the intermediate enzymes are localized in cytosol. The catalytic site of HMOX recognizes metalloporphyrins with central metal atoms other than iron; it favors some of these metalloporphyrins over heme as a potential substrate, sometimes by a large factor, permitting the synthetic heme analogue to serve as a potent competitive inhibitor of HMOX reaction. Since these synthetic metalloporphyrins do not bind molecular oxygen, they are not metabolically degraded by ring rupture and do not add to the body pool of bile pigment. One possible consequence of this competitive inhibition of heme degradation is suppression of bile pigment formation to such a degree that excessive plasma levels of bilirubin may be diminished. The studies of Drummond and Kappas (1981) and later studies in rats, mice, monkeys, and man, and also our studies have proved the latter phenomenon. The compound does not appear to affect the metabolic disposition of preformed bilirubin but inhibits biliary bilirubin excretion derived from the metabolism of endogenous or exogenous heme. Whether some of the effect of Sn-PP on naturally occurring or experimentally induced jaundice in animals reflects diversion of heme to nonheme to oxygenase-dependent pathways of heme metabolism, or whether a pathway which is normally latent becomes activated concurrent with HMOX inhibition is not known.(ABSTRACT TRUNCATED AT 400 WORDS)
Beri
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Department of Chemistry, University of Delhi, India.
Chandra
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D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006932:Hyperbilirubinemia / Q000517:prevention & control; D007231:Infant, Newborn; D007855:Lead Poisoning / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology*; D008670:Metals / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D014443:Tyrosine
D008665:Metalloporphyrins; D008670:Metals; D009942:Organometallic Compounds; D014443:Tyrosine; D006418:Heme; D003577:Cytochrome P-450 Enzyme System