Structure-Function Relationships in Flavoenzyme-dependent Amine Oxidations

Abstract

polyamine oxidase monoamine oxidase Amine oxidations are important in a number of basic biological processes ranging from lysyl oxidation in the cross-linking of collagen to the degradative metabolism of polyamines and neurotransmitters. The oxidations of biogenic amines to the corresponding imines are catalyzed by either the quinoprotein class of enzymes (usually primary amines) (1Hartmann C. McIntire W.S. Methods Enzymol. 1997; 280: 98-150Crossref PubMed Scopus (15) Google Scholar) or by the flavin-containing amine oxidases (primary, secondary, or tertiary amines) (2Massey V. Biochem. Soc. Trans. 2000; 28: 283-296Crossref PubMed Google Scholar). In both cases, molecular oxygen is the usual electron acceptor with hydrogen peroxide formed as reaction product. Flavin amine oxidases (2Massey V. Biochem. Soc. Trans. 2000; 28: 283-296Crossref PubMed Google Scholar) catalyze the oxidation of amines via an oxidative cleavage of the α-CH bond of the substrate to form an imine product with the concomitant reduction of the flavin cofactor (Fig. 1A). The imine product is then hydrolyzed (non-enzymatically in the cases investigated) to the corresponding aldehyde and ammonia (or amine for secondary or tertiary amine substrates). The reduced flavin coenzyme reacts with oxygen to form hydrogen peroxide and the oxidized form of the flavin to complete the catalytic cycle. The focus of this minireview is the structure and function of plant polyamine oxidase (PAO)1 and human monoamine oxidase (MAO), two thoroughly investigated members of the flavin-dependent class of amine oxidases. Both enzymes have been structurally characterized by x-ray crystallography (3Binda C. Coda A. Angelini R. Federico R. Ascenzi P. Mattevi A. Structure Fold Des. 1999; 7: 265-276Abstract Full Text Full Text PDF Scopus (163) Google Scholar, 4Binda C. Newton-Vinson P. Hubalek F. Edmondson D.E. Mattevi A. Nat. Struct. Biol. 2002; 9: 22-26Crossref PubMed Scopus (533) Google Scholar). Plant PAO is involved in the catabolism of polyamines (Fig.1 B) by catalyzing the oxidation of the secondary amino groups of spermine or spermidine and their acetyl derivatives (5Seiler N. Prog. Brain Res. 1995; 106: 333-344Crossref PubMed Scopus (124) Google Scholar). It is a soluble enzyme with a non-covalently bound FAD cofactor (6Sebela M. Radova A. Angelini R. Tavladoraki P. Frebort I.I. Pec P. Plant Sci. 2001; 160: 197-207Crossref PubMed Scopus (117) Google Scholar, 7Tavladoraki P. Schinina M.E. Cecconi F., Di Agostino S. Manera F. Rea G. Mariottini P. Federico R. FEBS Lett. 1998; 426: 62-66Crossref PubMed Scopus (91) Google Scholar). Very recently, the gene for human PAO has been identified (8Wang Y.L. Devereux W. Woster P.M. Stewart T.M. Hacker A. Casero R.A. Cancer Res. 2001; 61: 5370-5373PubMed Google Scholar), and the protein was investigated in preliminary work. Polyamines are essential for cell growth and differentiation (9Tabor C.W. Tabor H. Annu. Rev. Biochem. 1984; 53: 749-790Crossref PubMed Scopus (3233) Google Scholar), and their metabolism is the subject of extensive research to develop potential targets for antiproliferative drugs (10Casero R.A., Jr. Woster P.M. J. Med. Chem. 2001; 44: 1-26Crossref PubMed Scopus (218) Google Scholar). MAOs oxidize the primary amino groups of arylalkyl amines (Fig.1 C) and are widely distributed in higher eukaryotes. In mammals, MAO is present as two isoforms (MAO A and MAO B), which are separate gene products, that exhibit over 70% sequence identity and distinct but overlapping substrate specificities in the catabolism of neurotransmitters, such as dopamine and serotonin (11Weyler W. Hsu Y.P. Breakfield X. Pharmacol. Ther. 1990; 47: 391-417Crossref PubMed Scopus (291) Google Scholar,12Shih J.C. Chen K. Ridd M.J. Annu. Rev. Neurosci. 1999; 22: 197-217Crossref PubMed Scopus (1030) Google Scholar). Both MAO A and MAO B are implicated in a large number of neurological disorders and are a target for drugs against Parkinson's disease and depression (13Cesura A.M. Pletscher A. Prog. Drug Res. 1992; 38: 171-297PubMed Google Scholar). Mammalian MAOs are bound to the outer mitochondrial membrane and have a FAD molecule covalently bound to the protein via an 8α-thioether linkage to a cysteinyl residue (14Kearney E.B. Salach J.I. Walker W.H. Seng R.L. Kenney W. Zeszotek E. Singer T.P. Eur. J. Biochem. 1971; 24: 321-327Crossref PubMed Scopus (193) Google Scholar). They are expressed in both a tissue-dependent and an age-dependent manner and have been the subject of extensive clinical and pharmacological studies with more than 15,000 papers currently listed in the Medline index. A good deal of mechanistic information is available for these two isozymes (see below). The recent determination of the crystal structures of plant PAO and human MAO B have revealed valuable insights into the structure-function of the flavin-dependent amine oxidases. PAO (472 residues) and MAO B (520 residues) share ∼20% amino acid sequence identity that is d