Dataset Information

Human copper-dependent amine oxidases.

ABSTRACT: Copper amine oxidases (CAOs) are a class of enzymes that contain Cu(2+) and a tyrosine-derived quinone cofactor, catalyze the conversion of a primary amine functional group to an aldehyde, and generate hydrogen peroxide and ammonia as byproducts. These enzymes can be classified into two non-homologous families: 2,4,5-trihydroxyphenylalanine quinone (TPQ)-dependent CAOs and the lysine tyrosylquinone (LTQ)-dependent lysyl oxidase (LOX) family of proteins. In this review, we will focus on recent developments in the field of research concerning human CAOs and the LOX family of proteins. The aberrant expression of these enzymes is linked to inflammation, fibrosis, tumor metastasis/invasion and other diseases. Consequently, there is a critical need to understand the functions of these proteins at the molecular level, so that strategies targeting these enzymes can be developed to combat human diseases.

SUBMITTER: Finney J

PROVIDER: S-EPMC5995473 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Human copper-dependent amine oxidases.

Finney Joel J Moon Hee-Jung HJ Ronnebaum Trey T Lantz Mason M Mure Minae M

Archives of biochemistry and biophysics 20140106

Copper amine oxidases (CAOs) are a class of enzymes that contain Cu(2+) and a tyrosine-derived quinone cofactor, catalyze the conversion of a primary amine functional group to an aldehyde, and generate hydrogen peroxide and ammonia as byproducts. These enzymes can be classified into two non-homologous families: 2,4,5-trihydroxyphenylalanine quinone (TPQ)-dependent CAOs and the lysine tyrosylquinone (LTQ)-dependent lysyl oxidase (LOX) family of proteins. In this review, we will focus on recent de ...[more]

PMID: 24407025

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Project description:The structural underpinnings of enzyme substrate specificity are investigated in a pair of copper amine oxidases (CAOs) from Hansenula polymorpha (HPAO-1 and HPAO-2). The X-ray crystal structure (to 2.0 A resolution) and steady state kinetic data of the second copper amine oxidase (HPAO-2) are presented for comparison to those of HPAO-1. Despite 34% sequence identity and superimposable active site residues implicated in catalysis, the enzymes vary considerably in their substrate entry channel. The previously studied CAO, HPAO-1, has a narrow substrate channel. In contrast, HPAO-2 has a wide funnel-shaped substrate channel, which also contains a side chamber. In addition, there are a number of amino acid changes within the channels of HPAO-2 and HPAO-1 that may sterically impact the ability of substrates to form covalent Schiff base catalytic intermediates and to initiate chemistry. These differences can partially explain the greatly different substrate specificities as characterized by k(cat)/K(m) value differences. In HPAO-1, the k(cat)/K(m) for methylamine is 330-fold greater than for benzylamine, whereas in HPAO-2, it is benzylamine that is the better substrate by 750-fold. In HPAO-2, an inflated (D)k(cat)/K(m)(methylamine) in relation to (D)k(cat)/K(m)(benzylamine) indicates that proton abstraction has been impeded more than substrate release. In HPAO-1, (D)k(cat)/K(m)(S) changes little with the slow substrate and indicates a similar increase in the energy barriers that control both substrate binding and subsequent catalysis. In neither case is k(cat)/K(m) for the second substrate, O(2), significantly altered. These results reinforce the modular nature of the active sites of CAOs and show that multiple factors contribute to substrate specificity and catalytic efficiency. In HPAO-1, the enzyme with the smaller substrate binding pocket, both initial substrate binding and proton loss are affected by an increase in substrate size, while in HPAO-2, the enzyme with the larger substrate binding pocket, the rate of proton loss is differentially affected when a phenyl substituent in the substrate is reduced to the size of a methyl group.

Project description:BACKGROUND: Polyamines (PAs) are oxidatively deaminated at their primary or secondary amino-groups by copper-containing amine oxidases (CuAOs) or FAD-dependent amine oxidases (PAOs), respectively. Both enzymes have long been considered to be apoplastic proteins. However, three out of five PAO isoforms in Arabidopsis thaliana are localized in peroxisomes, while the other two PAOs are predicted to be cytosolic. Interestingly, most of these PAOs do not contribute to terminal PA oxidation, but instead are involved in the back-conversion pathway, producing spermidine from spermine and putrescine from spermidine, which in turn is inhibited by putrescine. This opens the question as to whether PAs are catabolized in the apoplast of Arabidopsis and if the terminal oxidation occurs in the peroxisomes. The main objective of this study was to know if these catabolic processes are mediated by CuAOs. RESULTS: A. thaliana contains ten genes annotated as CuAOs, but only one (ATAO1) has been characterized at the protein level. Reported herein is the characterization of three genes encoding putative Arabidopsis CuAOs (AtCuAO1, AtCuAO2 and AtCuAO3). These genes encode functional CuAOs that use putrescine and spermidine as substrates. AtCuAO1, like ATAO1, is an extracellular protein, while AtCuAO2 and AtCuAO3 are localized in peroxisomes. The three genes present a different expression profile in response to exogenous treatments, such as application of abcisic acid, methyl jasmonate, salycilic acid, flagellin 22 and wounding. CONCLUSIONS: PA catabolism in the Arabidopsis apoplast is mediated predominantly by CuAOs, while in peroxisomes the co-localization of CuAO-dependent terminal catabolism with PAO-back-conversion machineries might contribute to modulating putrescine-mediated inhibition of the back-conversion, suggesting the occurrence of a tight coordination between both catabolic pathways. The expression profile of AtCuAO1-3 in response to different exogenous treatments, together with the different localization of the corresponding proteins, provides evidence for the functional diversification of Arabidopsis CuAO proteins.

Dataset Information

Human copper-dependent amine oxidases.

Publications

Human copper-dependent amine oxidases.

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