We are working with 1) the flavocytochrome - para-cresol methylhydroxylase (PCMH), 2) the copper/quinoproteins - human diamine oxidase (HDAO), human monamine oxidase (HMAO), and bacterial beta-phenylethylamine oxidase (PEAO), and 3) bacterial quinoprotein - methylamine dehydrogenase (MADH). We have crystal structures for PCMH, PEAO and MADH. The genes for each have been cloned, sequenced and heterologously expressed, and site-specific mutagenesis experiments have been initiated. We will use computer graphics, computer-aided modeling, and computational chemistry to study electron transfer, enzyme binding of substrates, inhibitors, activators, and monovalent cations, enzyme catalysis, etc. We will use the structures of PEAO and a plant diamine oxidase to model the structures of HDAO and HMAO for the purpose of computer-aided design of drug targeting these oxidase. These drugs may find use in treating various parasitic infections, and should help decipher the true function of these enzyme in man. This work may also be useful in the treatment of cancer, developmental diseases, for wound healing, and aid in the understanding of apoptosis. The use of the Computer Graphics Laboratory facilities is necessary for this work.
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