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PDBsum entry 4zcc
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Oxidoreductase
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PDB id
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4zcc
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References listed in PDB file
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Key reference
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Title
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Bacterial renalase: structure and kinetics of an enzyme with 2- And 6-Dihydro-β-Nad(p) oxidase activity from pseudomonas phaseolicola.
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Authors
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M.R.Hoag,
J.Roman,
B.A.Beaupre,
N.R.Silvaggi,
G.R.Moran.
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Ref.
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Biochemistry, 2015,
54,
3791-3802.
[DOI no: ]
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PubMed id
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Abstract
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Despite a lack of convincing in vitro evidence and a number of sound
refutations, it is widely accepted that renalase is an enzyme unique to animals
that catalyzes the oxidative degradation of catecholamines in blood in order to
lower vascular tone. Very recently, we identified isomers of β-NAD(P)H as
substrates for renalase (Beaupre, B. A. et al. (2015) Biochemistry, 54,
795-806). These molecules carry the hydride equivalent on the 2 or 6 position of
the nicotinamide base and presumably arise in nonspecific redox reactions of
nicotinamide dinucleotides. Renalase serves to rapidly oxidize these isomers to
form β-NAD(P)(+) and then pass the electrons to dioxygen, forming H2O2. We have
also shown that these substrate molecules are highly inhibitory to dehydrogenase
enzymes and thus have proposed an intracellular metabolic role for this enzyme.
Here, we identify a renalase from an organism without a circulatory system. This
bacterial form of renalase has the same substrate specificity profile as that of
human renalase but, in terms of binding constant (Kd), shows a marked preference
for substrates derived from β-NAD(+). 2-dihydroNAD(P) substrates reduce the
enzyme with rate constants (kred) that greatly exceed those for 6-dihydroNAD(P)
substrates. Taken together, kred/Kd values indicate a minimum 20-fold preference
for 2DHNAD. We also offer the first structures of a renalase in complex with
catalytically relevant ligands β-NAD(+) and β-NADH (the latter being an
analogue of the substrate(s)). These structures show potential electrostatic
repulsion interactions with the product and a unique binding orientation for the
substrate nicotinamide base that is consistent with the identified activity.
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