Harpers

HHBIOLOGIC OXIDATION / 89HFigure 11–4. Mechanism of oxidationand reduction of nicotinamide coenzymes.There is stereospecificity aboutposition 4 of nicotinamide when it is reducedby a substrate AH 2 . One of the hydrogenatoms is removed from the substrateas a hydrogen nucleus with twoelectrons (hydride ion, H − ) and is transferredto the 4 position, where it may beattached in either the A or the B positionaccording to the specificity determinedby the particular dehydrogenase catalyzingthe reaction. The remaining hydrogenof the hydrogen pair removed fromthe substrate remains free as a hydrogenion.H4+NRCONH 2AH 2NAD + + AH 2DEHYDROGENASESPECIFIC FOR AAH 2A + H +DEHYDROGENASESPECIFIC FOR BNADH + H + + A4NR4NRHCONH 2A FormCONH 2B FormPeroxisomes are found in many tissues, including liver.They are rich in oxidases and in catalase, Thus, the enzymesthat produce H 2 O 2 are grouped with the enzymethat destroys it. However, mitochondrial and microsomalelectron transport systems as well as xanthine oxidasemust be considered as additional sources of H 2 O 2 .OXYGENASES CATALYZE THE DIRECTTRANSFER & INCORPORATIONOF OXYGEN INTO A SUBSTRATEMOLECULEOxygenases are concerned with the synthesis or degradationof many different types of metabolites. They catalyzethe incorporation of oxygen into a substrate moleculein two steps: (1) oxygen is bound to the enzyme atthe active site, and (2) the bound oxygen is reduced ortransferred to the substrate. Oxygenases may be dividedinto two subgroups, as follows.Dioxygenases Incorporate Both Atomsof Molecular Oxygen Into the SubstrateThe basic reaction is shown below:A+ O →AOExamples include the liver enzymes, homogentisatedioxygenase (oxidase) and 3-hydroxyanthranilatedioxygenase (oxidase), that contain iron; and L-tryptophandioxygenase (tryptophan pyrrolase) (Chapter30), that utilizes heme.Monooxygenases (Mixed-FunctionOxidases, Hydroxylases) IncorporateOnly One Atom of Molecular OxygenInto the SubstrateThe other oxygen atom is reduced to water, an additionalelectron donor or cosubstrate (Z) being necessaryfor this purpose.A— H+ O2+ ZH2→ A—OH+ H2O+ ZCytochromes P450 Are MonooxygenasesImportant for the Detoxification of ManyDrugs & for the Hydroxylation of SteroidsCytochromes P450 are an important superfamily ofheme-containing monooxgenases, and more than 1000such enzymes are known. Both NADH and NADPHdonate reducing equivalents for the reduction of thesecytochromes (Figure 11–5), which in turn are oxidizedby substrates in a series of enzymatic reactions collectivelyknown as the hydroxylase cycle (Figure 11–6). In livermicrosomes, cytochromes P450 are found together withcytochrome b 5 and have an important role in detoxifica-2 2tion. Benzpyrene, aminopyrine, aniline, morphine, andbenzphetamine are hydroxylated, increasing their solubilityand aiding their excretion. Many drugs such as phenobarbitalhave the ability to induce the formation of microsomalenzymes and of cytochromes P450.Mitochondrial cytochrome P450 systems are foundin steroidogenic tissues such as adrenal cortex, testis,ovary, and placenta and are concerned with the biosyn-