Oxygen activating heme enzymes

Studies on the oxygen activation mechanisms by new heme enzymes using hemoprotein mutants and synthetic heme models 96YGK1046. 

Oxygen activation is a central theme in biochemistry and is performed by a wide range of different iron and copper enzymes. In addition to our studies of the dinuclear non-heme iron enzymes MMO and RNR, we also studied oxygen activation in the mononuclear non-heme iron enzyme isopenicillin N synthase (IPNS). This enzyme uses O2 to transform its substrate ACV to the penicillin precursor isopenicillin N [53], a key step in the synthesis of the important P-lactam antibiotics penicillins and cephalosporins [54, 55],... 

Endogenous NO is produced almost exclusively by L-arginine catabolism to L-citrul-line in a reaction catalyzed by a family of nitric oxide synthases (NOSs) [3]. In the first step, Arg is hydroxylated to an enzyme-bound intermediate "-hydroxy-1.-arginine (NHA), and 1 mol of NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) and O2 are consumed. In the second step, N H A is oxidized to citrulline and NO, with consumption of 0.5 mol of NADPH and 1 mol of 02 (Scheme 1.1). Oxygen activation in both steps is carried out by the enzyme-bound heme, which derives electrons from NADPH. Mammalian NOS consists of an N-terminal oxy-... 

Cytochrome c can easily be extracted from tissue particles by dilute salt solutions. It was isolated by Keilin and Hartree in 1930 and shown to contain a porphyrin ring structure. In 1933 Zeilen and Reuter established that cytochrome c was a heme (iron-porphyrin) protein. Slightly different forms of cytochrome a were distinguished in yeast and bacteria by Keilin in 1934 and the different properties of cytochrome a and a3 by Tamiya et al. in 1937. The identity of cytochrome 03, the enzyme which activates oxygen with Warburg s atmungsferment, was proposed by Keilin in 1939. Cytochrome a/a3 was renamed cytochrome oxidase by Malcolm Dixon (1939). The oxidation route then offered was ... 

Thus, in this heme paradigm, the porphyrin plays an active role in accessing the high-valent oxidation state required for the substrate oxidations. Many of the proposed mechanisms for the nonheme iron oxygen activating enzymes follow this mechanistic model. An important question is how analogous chemical reactions can be carried out in the absence of a porphyrin ligands alternatively, what... 

The focus of this chapter is the reaction site of oxygenases (hemo-proteins) having heme as the prosthetic group. We discuss the oxygen activation in tryptophan pyrrolase (TPO) and cytochrome P-450 based on our experimental results using iron-porphyrin complexes as the model for the active site of these enzymes. 

Thus, COET is important as the oxygen-activation process not only in heme enzymes but also in other biological systems such as the bleomycin-Fe(II)-02 system. 

Flavin-dependent le -transfer in enzymes and chemical model systems can he differentiated from 2e -transfer activities, i.e., (de)hydrogenation and oxygen activation, by chemical structure and dynamics. For le -transfer, two types of contacts are discussed, namely outer sphere for interflavin and flavin-heme and inner sphere for flavinr-fenedoxin contacts. Flavin is the indispensable mediator between 2e - and le -transfer in all biological redox chains, and there is a minimal requirement of three cooperating redox-active sites for this activity. The switch between 2e - and le -transfer is caused by apoprotein-dependent prototropy between flavin positions N(l)/0(2a) and N(5) or by N(5)-metal contact. 

Fig. 21. Typical intermediates in hemoprotein enzyme active sites. The iron protoporphyrin IX cofactor (heme) forms dioxygen adducts termed oxy-species. In the course of oxygen activation and catalytic redox transformations, the oxy form can be consecutively converted into hydroperoxo- and oxo-type intermediates, which are usually referred to as compound 0, compound I, and compound II. Reproduced with permission from Ref (183). Copyright Nature Publishing Group.

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