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Amine oxidase and its catalytic activity
- 1. AMINE OXIDASE SHIVANI SINGH 2015IMSCH020 CENTRAL UNIVERSITY OF RAJASTHAN
- 2. INTRODUCTION • catalyze the oxidation of biogenic amines • There are two classes of amine oxidases: 1. flavin-containing 2. copper-containing • RCH2NH2 + H2O + O2 = RCHO + NH3 + H2O2 • AOs allow prokaryotes and fungi to use primary amines as sole sources of nitrogen for growth. • In plants- synthesis of alkaloids , cell wall formation, and wound healing • TPQ is the cofactor required.
- 3. CRYSTAL STRUCTURE OF AMINE OXIDASE • Bacterial amine oxidase • the TPQ is coordinated directly to the Cu, creating a distorted tetrahedral environment • In many structures of CAOs, the TPQ is disordered, further emphasizing the conformational flexibility of this ligand. • The three His ligands of the Cu are conserved • When the TPQ is not coordinated directly to the Cu, one or two water ligands are bound to the Cu.
- 4. Fig:1 Bacterial Amine oxidase, https://en.wikipedia.org/wiki/Amine_oxidase_(copper- containing)#/media/File:PDB_1d6u_EBI.jpg
- 5. AMINE OXIDASE FROM BOVINE SERUM • 3 domains- D2, D3 and D4 • 746 amino acids long • D2 and D3 domains are small ( four or five strands and two α-helices each) • D2 comprises residues from 57 to 161 • Domain D4 comprises about 400 residues
- 7. • Copper AO occurs as mushroom shaped homodimers of 70-95 kDa • each monomer containing a copper(II) and covalently bound redox cofactor, TPQ • copper ion coordinated with three histidine residues and two water molecules at axial site in a distorted square pyramidal geometry.
- 9. • STEP 2 • Inner-Sphere (A → C) Pathway for Electron Transfer during the Oxidative Half-Reaction
- 10. OTHER FUNCTIONS INVOLVING HYDROGEN PEROXIDE • Promotion of Glucose up-take • Cell Death • Vascular Adhesion • Cellular maturation and extracellular matrix formation • Signaling • Self-regulation
- 11. SHORT HISTORICAL OVERVIEW OF COPPER AMINE OXIDASE INHIBITOR STUDIES • Zeller (1940), first demonstrated that pig kidney amine oxidase (PKAO) was inhibited by cyanide, attributed this inhibition to the presence of a carbonyl compound in the prosthetic group of the enzyme. • Mann (1961) worked with a pure pea seedling amine oxidase (PSAO). In ensuing research, various copper-chelating agents were characterized as inhibitors of the pea enzyme
- 12. PHARMACOLOGICAL APPLICATIONS Implications of ControllIng bzAO activity in diabetes: the present • increased plasma levels of BzAO occurring in diabetes patients • Increased plasma BzAO levels are correlated with glycated hemoglobin • circulating BzAO has also been proposed as an independent prognostic marker for mortality in heart failure • suggesting a relationship of plasma enzyme activity, the duration of diabetes, and its cardiovascular complications
- 13. ssAO activity and neurodegenerative Diseases: Evidence for future Pharmacological implications? • AD patients exhibit increased membrane-bound SSAO levels • Increased plasma levels of BzAO in AD patients may indicate insulin resistance, and membrane-bound SSAO inhibitors may trigger β- amyloid peptide polymerization • Membrane-bound SSAO activity may act as an initiating factor for protein fibrillation, a typical manifestation of this disease.
- 14. COPPER AMINE OXIDASES AS ANTIOXIDANT AND CARDIOPROTECTIVE AGENTS • The in vitro scavenging effects of serum amine oxidases (SAOs) were compared with those of ceruloplasmin (CP) and superoxide dismutase (SOD) • Purified BSAO and CP (1 µM) were the best antioxidants in vitro (~90% scavenging capacity). At equal concentration, SOD presented only 12.8% scavenging • OCl–, HOCl, and Cl generated by electrolysis, SAO showed best scavenging and better recovery for cardiovascular muscles.
- 15. THANK YOU
- 16. REFERENCES • Floris, G., & Mondovì, B. (2009). Copper amine oxidases: Structures, catalytic mechanisms, and role in pathophysiology. Boca Raton: CRC Press
Editor's Notes
- Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. Both these enzymes convert amines to aldehyde and peroxide. A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. These are found in bacteria, fungi, plants and animals.
- Crystal structures of copper-containing amine oxidases (CAOs) have been solved from eubacteria, plants, yeasts and mammals including humans cofactor for oxidation which has been identified as TPQ (Topaquinone =paraquinone form of trihydroxyphenylalanine
- crystal structure of e. coli amine oxidase anaerobically reduced with beta-phenylethylamine Class: All beta proteins • Fold: Supersandwich• Superfamily: Amine oxidase catalytic domain• Family: Amine oxidase catalytic domain• Protein Domain: Copper amine oxidase, domain 3
- The yellowish pink color of CAOs stems from an intense absorption band in the 460- to 500-nm region assigned to TPQox. The weak d–d bands of the Cu(II) centers are hidden in the intense TPQox. The active site is buried and requires a conformational change to allow the substrate access
- Sq pyramidal or distorted tetrahedral
- 1. Cu(II)–TPQox (A) reacts with a primary amine to form a quinoneimine “substrate Schiff base” (TPQSSB). 2. Then the conversion of TPQSSB to a quinolaldimine “product Schiff base” ( TPQPSB), facilitated by α-carbon proton abstraction by a conserved aspartate. 3. The aldehyde product is then released via hydrolysis, generating the reduced aminoquinol Cu(II). 4. Analogs, such as 2-hydrazinopyridine (2-HP), benzylhydrazine, and tranylcypromine, have been used to structurally model enzyme–substrate complexes and indicate that TPQ must be in an “off”-copper conformation with the C5 carbonyl of TPQ positioned toward the conserved aspartate that facilitates stereospecific proton abstraction.
- O2binds to the Cu(I) center of Cu(I)–TPQSQ and is reduced to O2•– by a non-rate-limiting inner-sphere electron transfer process. Coordinated water facilitates redox-related changes in coordination geometry, and this has been confirmed by X-ray absorption spectroscopic analysis of the Cu(I) state. PCET proton coupled e transfer
- Hydrogen peroxide is known to mimic the effects of insulin by causing a recruitment of the intracellular GLUT4 glucose transporter to cell surfaces All these enzymes produce H2O2 as a product of amine oxidation. Although it is an important cellular signaling molecule, H2O2 is toxic at higher concentrations and linking it to cell death under pathophysiological conditions has become a popular pastime. Endothelial PrAO also functions as a vascular-adhesion protein (VAP-1). also has a chemotactic function in inducing the directional migration of vascular smooth muscle cells.
- Historically, two key points have guided the development of inhibitors of CAOs, namely the two prosthetic groups of these enzymes: the organic active carbonyl cofactor responsible for oxidative deamination of primary amine substrates and the active site copper (cupric ion). Indeed, most inhibitors of the enzymes act at one or the other of these two active-site entities. It has long been known that the enzymes are inhibited by carbonyl reagents such as hydrazine and semicarbazide. Cyanohydrin reaction
- Plasma BzAO (benzyl amine oxidase) may be indicative of the metabolic aspects of endothelial dysfunction and of changes in glucose homeostasis. Because subclinical, asymptomatic, endothelial dysfunction is hard to detect, an understanding of BzAO timing in the circulation is crucial to investigating its prognostic value.
- Alzhiemer disease semi carbazide sensitive amine oxidase Cerebral amyloid angiopathy characterized by the deposition of β-amyloid in brain vessels, inducing the degeneration of vascular smooth muscle and endothelial cells, is considered a crucial event in Alzheimer’s disease (AD) pathogenesis Therefore, inhibition of membrane-bound SSAO may prevent local increases of aldehydes, thus reducing the pro-inflammatory potential of such compounds. If that hypothesis is correct, AD therapy including inhibitors of membrane-bound SSAO may become a primary prevention strategy.
- , both known as reactive oxygen species (ROS) scavengers
- even though these enzymes have been studied for over 50 years, much more basic biochemical work is needed before we can understand the mechanism of action, physiological significance, and interrelationship of these functionally related series of enzymes.