Structure–Activity Relationships of SSAO/VAP‐1 Arylalkylamine‐Based Substrates

Yraola, Francesc; Zorzano, António; Alberício, Fernando; Royo, Míriam

doi:10.1002/cmdc.200800393

Cited by 15 publications

(7 citation statements)

References 66 publications

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“…In mammals, among the SSAOs, vascular adhesion protein 1 is one of the most extensively studied members of this group of enzymes (119,202,524). It is interesting that some monoamine oxidase inhibitors such as phenelzine with antidepressant properties (20) are able to protect neurons and astrocytes against formaldehyde (424).…”

Section: Second Phase Of Methanol Catabolismmentioning

confidence: 99%

Metabolic Methanol: Molecular Pathways and Physiological Roles

Dorokhov

Shindyapina

Sheshukova

et al. 2015

Physiological Reviews

173

125

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Methanol has been historically considered an exogenous product that leads only to pathological changes in the human body when consumed. However, in normal, healthy individuals, methanol and its short-lived oxidized product, formaldehyde, are naturally occurring compounds whose functions and origins have received limited attention. There are several sources of human physiological methanol. Fruits, vegetables, and alcoholic beverages are likely the main sources of exogenous methanol in the healthy human body. Metabolic methanol may occur as a result of fermentation by gut bacteria and metabolic processes involving S-adenosyl methionine. Regardless of its source, low levels of methanol in the body are maintained by physiological and metabolic clearance mechanisms. Although human blood contains small amounts of methanol and formaldehyde, the content of these molecules increases sharply after receiving even methanol-free ethanol, indicating an endogenous source of the metabolic methanol present at low levels in the blood regulated by a cluster of genes. Recent studies of the pathogenesis of neurological disorders indicate metabolic formaldehyde as a putative causative agent. The detection of increased formaldehyde content in the blood of both neurological patients and the elderly indicates the important role of genetic and biochemical mechanisms of maintaining low levels of methanol and formaldehyde.

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Section: Second Phase Of Methanol Catabolismmentioning

confidence: 99%

Metabolic Methanol: Molecular Pathways and Physiological Roles

Dorokhov

Shindyapina

Sheshukova

et al. 2015

Physiological Reviews

173

125

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“…This increase in distance between the substituent and the C␣ atom attenuates field/inductive effects (45). The size of the active site cavity of VAP-1, in particular Leu-469, has been suggested to limit the size of VAP-1 substrates (46). In an effort to visualize the implications of para-substitution in the enzyme active site, structures of VAP-1 with benzylamine or phenylethylamine bound in the substrate Schiff base form (based on Protein Data Bank code: 2C11 (30)) were modeled and energy-minimized.…”

Section: Dependence Of Apparent K Cat /K M and D (K Cat /K M ) On Solmentioning

confidence: 99%

“…Therefore, care should be taken with the development and analysis of novel substrates and inhibitors for VAP-1. A detailed knowledge of the kinetic mechanism of VAP-1 will aid in the development of new substrates and inhibitors as potential treatments for several pathological conditions (12,46,49).…”

Section: Dependence Of Apparent K Cat /K M and D (K Cat /K M ) On Solmentioning

confidence: 99%

Reaction of Vascular Adhesion Protein-1 (VAP-1) with Primary Amines

Heuts

Gummadova

Pang

et al. 2011

Journal of Biological Chemistry

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Human vascular adhesion protein-1 (VAP-1) is an endothelial copper-dependent amine oxidase involved in the recruitment and extravasation of leukocytes at sites of inflammation. VAP-1 is an important therapeutic target for several pathological conditions. We expressed soluble VAP-1 in HEK293 EBNA1 cells at levels suitable for detailed mechanistic studies with model substrates. Using the model substrate benzylamine, we analyzed the steady-state kinetic parameters of VAP-1 as a function of solution pH. We found two macroscopic pK a values that defined a bell-shaped plot of turnover number k cat,app as a function of pH, representing ionizable groups in the enzyme-substrate complex. The dependence of (k cat /K m ) app on pH revealed a single pK a value (ϳ9) that we assigned to ionization of the amine group in free benzylamine substrate. A kinetic isotope effect (KIE) of 6 to 7.6 on (k cat /K m ) app over the pH range of 6 to 10 was observed with d 2 -benzylamine. Over the same pH range, the KIE on k cat was found to be close to unity. The unusual KIE values on (k cat / K m ) app were rationalized using a mechanistic scheme that includes the possibility of multiple isotopically sensitive steps. We also report the analysis of quantitative structure-activity relationships (QSAR) using para-substituted protiated and deuterated phenylethylamines. With phenylethylamines we observed a large KIE on k cat,app (8.01 ؎ 0.28 with phenylethylamine), indicating that C-H bond breakage is limiting for 2,4,5-trihydroxyphenylalanine quinone reduction. Poor correlations were observed between steady-state rate constants and QSAR parameters. We show the importance of combining KIE, QSAR, and structural studies to gain insight into the complexity of the VAP-1 steady-state mechanism.Copper amine oxidases or semicarbazide-sensitive amine oxidases (CAOs/SSAOs 3 ; EC 1.4.3.21/EC 1.4.3.22) comprise a group of copper-dependent enzymes that catalyze the oxidative deamination of primary amines to the corresponding aldehydes with concomitant release of hydrogen peroxide and ammonia. (R is a phenyl moiety in case of benzylamine and a benzyl moiety in case of phenylethylamine.)From the viewpoint of structure and mechanism, copper-dependent amine oxidases have been researched extensively for several decades, but relatively little is known about their physiological function.Human vascular adhesion protein-1 (VAP-1) is a dimeric membrane bound and circulating protein that is encoded by the AOC3 gene and is expressed mainly in endothelial cells of blood vessels, adipocytes, and smooth muscle cells (1-3). VAP-1 is a protein comprising two structural domains: an adhesive domain that targets leukocytes for transmigration and an amine oxidase domain (2, 4). At sites of inflammation on the endothelial cell surface, VAP-1 is involved in the recruitment and extravasation of lymphocytes and neutrophils. VAP-1 activity generates important signaling compounds such as hydrogen peroxide (5, 6). SSAO activity is also involved in glucose transport in adipose cells (1...

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“…A large number of additional amines have been identified as CAO substrates, including methylamine, ethylamine, aminoacetone, benzylamine, phenylethylamine, agmatine, spermine, spermidine, histamine, tyramine, mescaline, putrescine, and cadaverine [16–18]. …”

Section: Physiological Significance Of Caosmentioning

confidence: 99%

The Role of Protein Crystallography in Defining the Mechanisms of Biogenesis and Catalysis in Copper Amine Oxidase

Klema

Wilmot

2012

IJMS

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Copper amine oxidases (CAOs) are a ubiquitous group of enzymes that catalyze the conversion of primary amines to aldehydes coupled to the reduction of O2 to H2O2. These enzymes utilize a wide range of substrates from methylamine to polypeptides. Changes in CAO activity are correlated with a variety of human diseases, including diabetes mellitus, Alzheimer’s disease, and inflammatory disorders. CAOs contain a cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ), that is required for catalytic activity and synthesized through the post-translational modification of a tyrosine residue within the CAO polypeptide. TPQ generation is a self-processing event only requiring the addition of oxygen and Cu(II) to the apoCAO. Thus, the CAO active site supports two very different reactions: TPQ synthesis, and the two electron oxidation of primary amines. Crystal structures are available from bacterial through to human sources, and have given insight into substrate preference, stereospecificity, and structural changes during biogenesis and catalysis. In particular both these processes have been studied in crystallo through the addition of native substrates. These latter studies enable intermediates during physiological turnover to be directly visualized, and demonstrate the power of this relatively recent development in protein crystallography.

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Structure–Activity Relationships of SSAO/VAP‐1 Arylalkylamine‐Based Substrates

Cited by 15 publications

References 66 publications

Metabolic Methanol: Molecular Pathways and Physiological Roles

Metabolic Methanol: Molecular Pathways and Physiological Roles

Reaction of Vascular Adhesion Protein-1 (VAP-1) with Primary Amines

The Role of Protein Crystallography in Defining the Mechanisms of Biogenesis and Catalysis in Copper Amine Oxidase

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