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Information on EC 1.6.3.5 - renalase
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1.6.3.5 renalaseIUBMB Comments
Requires FAD. Renalase, previously thought to be a hormone, is a flavoprotein secreted into the blood by the kidney that oxidizes the 1,2-dihydro- and 1,6-dihydro- isomeric forms of beta-NAD(P)H back to beta-NAD(P)+. These isomeric forms, generated by nonspecific reduction of beta-NAD(P)+ or by tautomerization of beta-NAD(P)H, are potent inhibitors of primary metabolism dehydrogenases and pose a threat to normal respiration.
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Word Map
- 1.6.3.5
- hypertension
- renin
- angiotensin
- catecholamine
-
sprague-dawley
-
renin-angiotensin
- cardiac
-
normotensive
- cardiovascular
- arterial
- hypertrophy
-
sympathetic
-
glomerular
-
systolic
-
hansd
-
hannover
-
antihypertensive
- proteinuria
-
angiotensin-converting
- losartan
-
conscious
- glomerulosclerosis
- endothelin
-
ii-dependent
- angiotensinogen
- prorenin
-
tgrmren227
-
transgene-negative
-
end-organ
-
epoxyeicosatrienoic
-
renoprotective
-
nephrectomized
-
intrarenal
- perindopril
-
prehypertensive
-
dinucleotide-dependent
-
juxtaglomerular
-
extra-renal
- medicine
-
monogenetic
-
bosentan
-
bp-lowering
- valsartan
-
mren227
-
atrasentan
The enzyme appears in viruses and cellular organisms
Reaction Schemes
Synonyms
renalase, ren-2, ren-1, renalase-1, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
alphaNAD(P)H oxidase/anomerase
REN
renalase-1
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
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SYSTEMATIC NAME
IUBMB Comments
dihydro-NAD(P):oxygen oxidoreductase (H2O2-forming)
Requires FAD. Renalase, previously thought to be a hormone, is a flavoprotein secreted into the blood by the kidney that oxidizes the 1,2-dihydro- and 1,6-dihydro- isomeric forms of beta-NAD(P)H back to beta-NAD(P)+. These isomeric forms, generated by nonspecific reduction of beta-NAD(P)+ or by tautomerization of beta-NAD(P)H, are potent inhibitors of primary metabolism dehydrogenases and pose a threat to normal respiration.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2-dihydronicotinamide adenine dinucleotide phosphate + O2
?
-
-
?
6-dihydronicotinamide adenine dinucleotide phosphate + O2
?
-
-
?
1,2-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
?
1,2-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
1,6-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
?
1,6-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
alpha-NAD(P)H + H+ + O2
beta-NAD(P)+ + H2O2
-
renalase is selective for the alpha-anomer, which binds with a dissociation constant of about 20 microM. This association precedes monophasic two-electron reduction of the FAD cofactor with a rate constant of 40.2 per s. The reduced enzyme then delivers both electrons to dioxygen in a second-order reaction with a rate constant of about 2900 per M and s. Renalase has modest affinity for its beta-NADP+ product, and the FAD cofactor has a reduction potential of -155 mV that is unaltered by saturating beta-NADP+. Data suggest that the products are formed and released in a kinetically ordered sequence, first beta-NADP+ then H2O2
?
alpha-NAD(P)H + H+ + O2
beta-NAD(P)+ + H2O2
renalase is a protein hormone secreted into the blood by the kidney that is reported to lower blood pressure and slow heart rate
-
?
alpha-NAD(P)H + H+ + O2
beta-NAD(P)+ + H2O2
the substrate alpha-dihydropyridyl ring is oxidized by transferring two electrons to the flavin cofactor and the configuration of the ribose C1 is converted from alpha to beta. The reduced FAD cofactor then reoxidizes by reacting with dioxygen to yield hydrogen peroxide
-
?
alpha-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
?
additional information
?
-
renalase has an extremely low diaphorase activity, displaying lower kcat but higher kcat/Km for NADH compared to NADPH
-
?
additional information
?
-
-
renalase has an extremely low diaphorase activity, displaying lower kcat but higher kcat/Km for NADH compared to NADPH
-
?
additional information
?
-
-
renalase does not catalyze the oxidation of catecholamines
-
?
additional information
?
-
renalase exhibits a preference for substrates derived from beta-NAD+ over those derived from beta-NADP+
-
?
additional information
?
-
renalase exhibits a preference for substrates derived from beta-NAD+ over those derived from beta-NADP+
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
alpha-NAD(P)H + H+ + O2
beta-NAD(P)+ + H2O2
renalase is a protein hormone secreted into the blood by the kidney that is reported to lower blood pressure and slow heart rate
-
-
?
1,2-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
-
?
1,2-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
1,6-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
-
?
1,6-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FAD
flavoprotein. The substrate alpha-dihydropyridyl ring is oxidized by transferring two electrons to the flavin cofactor and the configuration of the ribose C1 is converted from alpha to beta. The reduced FAD cofactor then reoxidizes by reacting with dioxygen to yield hydrogen peroxide
FAD
the FAD cofactor has a reduction potential of ?155 mV that is unaltered by saturating beta-NADP+
FAD
the FAD prosthetic group becomes slowly reduced when the enzyme is incubated with NADPH under anaerobiosis
FAD
-
only extracellular (circulating) renalase acts in a FAD-independent manner
additional information
a recognizable NADP-binding site is absent in the protein structure, enzyme shows poor affinity for, and poor reactivity towards, NADH and NADPH with Kd values of ca 2 mM
-
additional information
-
a recognizable NADP-binding site is absent in the protein structure, enzyme shows poor affinity for, and poor reactivity towards, NADH and NADPH with Kd values of ca 2 mM
-
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
substantial expression in interstitial and luteal cells of ovary. Expression increases in testes and ovaries as mice develop and is further enhanced in the ovaries of pregnant mice
brenda
besides kidney, renalase gene expression is detectable in the heart, skeletal muscle, and the small intestine
brenda
substantial expression spermatogenic cells of testis. Expression increases in testes and ovaries as mice develop
brenda
additional information
renalase is predominantly expressed in reproductive/steroidogenic systems, with particularly substantial expression in oocytes, granulosa, interstitial and luteal cells of ovary, spermatogenic cells of testis, and cortex of adrenal gland
brenda
besides kidney, renalase gene expression is detectable in the heart, skeletal muscle, and the small intestine
brenda
enzyme is secreted into the blood by the kidney. Gene expression is highest in the kidney
brenda
besides kidney, renalase gene expression is detectable in the heart, skeletal muscle, and the small intestine
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
dysregulated extracellular renalase signalling promotes tumour growth
physiological function
physiological function
renalase is a protein hormone secreted into the blood by the kidney that is reported to lower blood pressure
physiological function
-
renalase knockout mouse model to explore the mechanisms mediating renalase's effect on phosphate excretion. Compared with wild-type mice maintained on a regular diet, knockout mice show decreased serum phosphate and increased urinary phosphate excretion. Both wild-type and knocout mice respond similarly to phosphate restriction by increasing renal catechol-O-methyl transferase COMT-1 activity and markedly decreasing phosphate excretion. Only catechol-O-methyl transferase expression and activity are significantly increased in knockout mice. Urinary dopamine increases by twofold, whereas urinary l-DOPA excretion decreases by twofold in the knockout mouse
physiological function
-
administration of renalase lowers blood pressure and heart rate and also protects cells and organs against ischaemic and toxic injury. Independent of its enzymatic properties, renalase functions as a cytokine that provides protection to cells, tissues and organs by interacting with its receptor to activate protein kinase B, JAK/STAT, and the mitogen-activated protein kinase pathways. Extracellular renalase protects against renal injury, cardiac injury, and acute pancreatitis
physiological function
-
renalase degrades catecholamines contributing to blood pressure control
physiological function
-
renalase participates in the pathophysiological mechanism of cardiac dysfunction by down-regulating the activity of sympathetic nervous system and degrading the level of catecholamines. Renalase is strongly associated with type 1 diabetes, hypertension and ischemic diseases
physiological function
-
renalase protects the cardiomyocytes of Sprague-Dawley rats against ischemia and reperfusion injury by reducing myocardial cell necrosis and apoptosis
Show AA Sequence and Transmembrane Helices (1167 entries)
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Please use the AA Sequence and Transmembrane Helices Search for a specific query.
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PDB
SCOP
CATH
UNIPROT
ORGANISM
Pseudomonas savastanoi pv. phaseolicola (strain 1448A / Race 6)
Pseudomonas savastanoi pv. phaseolicola (strain 1448A / Race 6)
Pseudomonas savastanoi pv. phaseolicola (strain 1448A / Race 6)
Pseudomonas savastanoi pv. phaseolicola (strain 1448A / Race 6)
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
to 2.5 A resolution. Renalase adopts the p-hydroxybenzoate hydroxylase fold topology, comprising a Rossmann-fold-based flavin adenine dinucleotide-binding domain and a putative substrate-binding domain, the latter of which contains a five-stranded anti-parallel beta-sheet. A large cavity, facing the flavin ring, presumably represents the active site. The renalase active site is fully solvent exposed and lacks an aromatic cage for binding the substrate amino group
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, stable in PBS buffer (10 mM Na2HPO4, 2 mM KH2PO4, 2.7 mM KCl, 137 mM NaCl, pH 7.4), can be stored indefinitely
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
N-terminally His-tagged renalase isoform 1 is expressed in Escherichia coli. Heterologous expression of renalase in Escherichia coli results in significant inclusion body accumulation at all temperatures tested
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
gonadotropin-releasing hormone antagonist, cetrorelix, represses renalase expression in mice ovaries and testes
knockout of leptin, an effector and modulator of steroid hormones and reproduction, causes a dramatic increase of renalase expression in mice testes
renalase expression is significantly increased in cancers of the pancreas, bladder and breast and in melanoma
-
the secretion of renalase in both plasma and urine is increased in patients with chronic kidney disease
-
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
plasma concentration of renalase is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects
medicine
-
renalase deficiency is associated with increased renal dopamine synthesis, stimulated phosphate excretion, and moderately severe hypophosphatemia. The signal to increase renal dopamine synthesis is strong since it overcomes a compensatory increase in catechol-O-methyl transferase activity
medicine
renalase infusion in rats causes a decrease in cardiac contractility, heart rate, and blood pressure and prevents a compensatory increase in peripheral vascular tone
medicine
-
renalase is a cardiovascular drug for ischemia/ischemia reperfusion injury
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Beaupre, B.A.; Carmichael, B.R.; Hoag, M.R.; Shah, D.D.; Moran, G.R.
Renalase is an alpha-NAD(P)H oxidase/anomerase
J. Am. Chem. Soc.
135
13980-13987
2013
Homo sapiens (Q5VYX0)
brenda
Sizova, D.; Velazquez, H.; Sampaio-Maia, B.; Quelhas-Santos, J.; Pestana, M.; Desir, G.V.
Renalase regulates renal dopamine and phosphate metabolism
Am. J. Physiol. Renal Physiol.
305
F839-F844
2013
Mus musculus
brenda
Beaupre, B.A.; Hoag, M.R.; Carmichael, B.R.; Moran, G.R.
Kinetics and equilibria of the reductive and oxidative half-reactions of human renalase with alpha-NADPH
Biochemistry
52
8929-8937
2013
Homo sapiens (Q5VYX0), Homo sapiens
brenda
Xu, J.; Li, G.; Wang, P.; Velazquez, H.; Yao, X.; Li, Y.; Wu, Y.; Peixoto, A.; Crowley, S.; Desir, G.V.
Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure
J. Clin. Invest.
115
1275-1280
2005
Rattus norvegicus (Q5U2W9), Homo sapiens (Q5VYX0), Homo sapiens
brenda
Milani, M.; Ciriello, F.; Baroni, S.; Pandini, V.; Canevari, G.; Bolognesi, M.; Aliverti, A.
FAD-binding site and NADP reactivity in human renalase: a new enzyme involved in blood pressure regulation
J. Mol. Biol.
411
463-473
2011
Homo sapiens (Q5VYX0), Homo sapiens
brenda
Zhou, M.; Liang, T.; Wang, Y.; Jin, D.; Wang, J.; Jia, L.; Zhang, S.
Expression and tissue localization of renalase, a novel soluble FAD-dependent protein, in reproductive/steroidogenic systems
Mol. Biol. Rep.
40
3987-3994
2013
Mus musculus (A7RDN6)
brenda
Quelhas-Santos, J.; Serrao, M.P.; Soares-Silva, I.; Fernandes-Cerqueira, C.; Simoes-Silva, L.; Pinho, M.J.; Remiao, F.; Sampaio-Maia, B.; Desir, G.V.; Pestana, M.
Renalase regulates peripheral and central dopaminergic activities
Am. J. Physiol. Renal Physiol.
308
F84-F91
2015
Mus musculus
brenda
Beaupre, B.A.; Hoag, M.R.; Moran, G.R.
Renalase does not catalyze the oxidation of catecholamines
Arch. Biochem. Biophys.
579
62-66
2015
Homo sapiens
brenda
Beaupre, B.A.; Roman, J.V.; Hoag, M.R.; Meneely, K.M.; Silvaggi, N.R.; Lamb, A.L.; Moran, G.R.
Ligand binding phenomena that pertain to the metabolic function of renalase
Arch. Biochem. Biophys.
612
46-56
2016
Pseudomonas savastanoi pv. phaseolicola (Q48MT7), Pseudomonas savastanoi pv. phaseolicola 1448A (Q48MT7)
brenda
Moran, G.R.; Hoag, M.R.
The enzyme Renalase
Arch. Biochem. Biophys.
632
66-76
2017
Pseudomonas savastanoi (Q48MT7), Homo sapiens (Q5VYX0), Pseudomonas savastanoi 1448A (Q48MT7)
brenda
Severina, I.; Fedchenko, V.; Veselovsky, A.; Medvedev, A.
The history of renalase from amine oxidase to alpha-NAD(P)H-oxidase/anomerase
Biochemistry (Moscow)
10
97-109
2016
Homo sapiens (Q5VYX0)
brenda
Sonawane, P.J.; Gupta, V.; Sasi, B.K.; Kalyani, A.; Natarajan, B.; Khan, A.A.; Sahu, B.S.; Mahapatra, N.R.
Transcriptional regulation of the novel monoamine oxidase renalase Crucial roles of transcription factors Sp1, STAT3, and ZBP89
Biochemistry
53
6878-6892
2014
Homo sapiens
brenda
Hoag, M.R.; Roman, J.; Beaupre, B.A.; Silvaggi, N.R.; Moran, G.R.
Bacterial renalase structure and kinetics of an enzyme with 2- and 6-dihydro-beta-NAD(P) oxidase activity from Pseudomonas phaseolicola
Biochemistry
54
3791-3802
2015
Pseudomonas syringae, Pseudomonas syringae 1448A
brenda
Beaupre, B.A.; Hoag, M.R.; Roman, J.; Foersterling, F.H.; Moran, G.R.
Metabolic function for human renalase oxidation of isomeric forms of beta-NAD(P)H that are inhibitory to primary metabolism
Biochemistry
54
795-806
2015
Homo sapiens
brenda
Moran, G.R.
The catalytic function of renalase A decade of phantoms
Biochim. Biophys. Acta
1864
177-186
2016
Homo sapiens (Q5VYX0), Homo sapiens
brenda
Quelhas-Santos, J.; Soares-Silva, I.; Fernandes-Cerqueira, C.; Simoes-Silva, L.; Ferreira, I.; Carvalho, C.; Coentrao, L.; Vaz, R.; Sampaio-Maia, B.; Pestana, M.
Plasma and urine renalase levels and activity during the recovery of renal function in kidney transplant recipients
Exp. Biol. Med. (Maywood)
239
502-508
2014
Homo sapiens
brenda
Fedchenko, V.I.; Buneeva, O.A.; Kopylov, A.T.; Veselovsky, A.V.; Zgoda, V.G.; Medvedev, A.E.
Human urinary renalase lacks the N-terminal signal peptide crucial for accommodation of its FAD cofactor
Int. J. Biol. Macromol.
78
347-353
2015
Homo sapiens (Q5VYX0), Homo sapiens
brenda
Wang, Y.; Safirstein, R.; Velazquez, H.; Guo, X.J.; Hollander, L.; Chang, J.; Chen, T.M.; Mu, J.J.; Desir, G.V.
Extracellular renalase protects cells and organs by outside-in signalling
J. Cell. Mol. Med.
21
1260-1265
2017
Homo sapiens
brenda
Li, X.; Xie, Z.; Lin, M.; Huang, R.; Liang, Z.; Huang, W.; Jiang, W.
Renalase protects the cardiomyocytes of Sprague-Dawley rats against ischemia and reperfusion injury by reducing myocardial cell necrosis and apoptosis
Kidney Blood Press. Res.
40
215-222
2015
Rattus norvegicus
brenda
Fedchenko, V.; Kopylov, A.; Kozlova, N.; Buneeva, O.; Kaloshin, A.; Zgoda, V.; Medvedev, A.
Renalase secreted by human kidney HEK293T cells lacks its n-terminal peptide implications for putative mechanisms of renalase action
Kidney Blood Press. Res.
41
593-603
2016
Homo sapiens
brenda
Li, X.; Huang, R.; Xie, Z.; Lin, M.; Liang, Z.; Yang, Y.; Jiang, W.
Renalase, a new secretory enzyme Its role in hypertensive-ischemic cardiovascular diseases
Med. Sci. Monit.
20
688-692
2014
Homo sapiens
brenda
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