Heme oxygenase conversion

Figure 7 The mechanism of heme oxygenase conversion of heme (46) into-biliverdin (38).

Hydroperoxo-ferric complex in heme oxygenase reserves a special place among other heme enzymes being the main catalytically active intermediate on the first monooxygenation step of HO catalysis. Conversion of heme to biliverdin, catalyzed by HO, begins with reduction of the ferric heme iron, binding of dioxygen, and second reduction... 

Tenhumen, Raimo Marver, Harvey S. Schmid, Rudi THE ENZYMATIC CONVERSION OF HEME TO BILIRUBIN BY MICROSOMAL HEME OXYGENASE. PNAS,No. 61 748-755 1968. 

Tenhunen, R., Marver, H.S., Schmid, R. (1968). The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc. Natl Acad. Sci. USA 61 748-55. 

Figure 5 The multistep conversion of heme to a-biliverdin catalyzed by heme oxygenase. The electrons from NADPH are transferred to heme oxygenase by cytochrome P4S0 reductase or other electron donor proteins.

Thiram and other dithiocarbamates are metabolic poisons. The acute effects of thiram are very similar to that of carbon disulfide, supporting the notion that the common metabolite of this compound is responsible for its toxic effects. The exact mechanism of toxicity is still unclear, however it has been postulated that the intracellular action of thiram involves metabolites of carbon disulfide, causing microsome injury and cytochrome P450 disruption, leading to increased heme-oxygenase activity. The intracellular mechanism of toxicity of thiram may include inhibition of monoamine oxidase, altered vitamin Bg and tryptophan metabolism, and cellular deprivation of zinc and copper. It induces accumulation of acetaldehyde in the bloodstream following ethanol or paraldehyde treatment. Thiram inhibits the in vitro conversion of dopamine to noradrenalin in cardiac and adrenal medulla cell preparations. It depresses some hepatic microsomal demethylation reactions, microsomal cytochrome P450 content and the synthesis of phospholipids. Thiram has also been shown to have moderate inhibitory action on decarboxylases and, in fish, on muscle acetylcholinesterases. 

Heme oxygenase, which catalyzes the conversion of free heme groups to biliverdin and CO, functions as part of a microsomal electron transport system similar to that of cytochrome 1 450-(FP = NADPH-cytochrome P450 reductase.) Heme oxygenase requires 3 02 and 5 NADPH. Biliverdin reductase can use NADPH or NADH as a reductant. 

Schutta, H.S. and Johnson, L. (1971). Fine structure observations on acute bilirubin encephalopathy in Gunn rats induced by sulfadimethoxine. Lab. Invest. 24 82-96 Siegfied, E.C., Stone, M.S., Madison, K.C. (1992). Ultraviolet light burn a cutaneous complication of visible light phototherapy of neonatal jaundice. Pediatr. Dermatol. 9 (3) 278-282 Tenhunen, R., Marver, H.S., and Schmid, R. (1968). The enzymatic conversion of heme to bilimbin by microsomal heme oxygenase. Proc. Natl. Acad. Sci. USA. 61 748-755... 

In the first step of the heme branch, protoporphyrin IX ferrochelatase (FeCh) inserts Fe + into protoporphyrin IX to produce protoheme (Figure 5.37). Heme oxygenase catalyzes the oxidation and the ring opening of protoheme to give biliverdin EXa. This reaction is followed by the conversion to (3 )-phytochromobilin controlled by phytochromobilin synthase. Isomerization of 3 -phytochromobilin into the (3Z) isomer takes place before the chromophore is bound to the phytochrome apoprotein. Whether such an isomerization step is catalyzed by an enzyme or whether it proceeds spontaneously remained unknown [137]. 

Studies of bilirubin formation with tracers, using bile fistula animals, or isolated whole liver, have revealed that there are several sources of bilirubin (Table 1). One is a very early labeled bilirubin (ELB) with a half-life of a few hours derived from the conversion by the liver of exogenous tracer ALA via heme to bilirubin. The labeled bilirubin appeared [Israels et al., 94] 15 minutes after injection of tracer ALA into the rat the bilirubin increased to a maximum in 60 minutes. Both the liver and the kidney converted ALA to bilirubin, but the liver was the main contributor. When protein synthesis of the liver was blocked by cycloheximide to prevent new hemoprotein synthesis, ELB still continued to be formed. This experiment suggests that heme does not have to be attached to a hemoprotein other than heme oxygenase to be rapidly oxidized. Thus, the earliest fraction of labeled bilirubin may be... 

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