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Enzyme Nomenclature
Information on EC 1.6.3.5 - renalase
for references in articles please use BRENDA:EC1.6.3.5
Word Map on EC 1.6.3.5
- 1.6.3.5
- hypertension
- renin
- angiotensin
-
sprague-dawley
-
renin-angiotensin
- cardiac
- catecholamine
- cardiovascular
-
normotensive
- hypertrophy
- arterial
-
blockade
-
systolic
-
glomerular
-
sympathetic
-
antihypertensive
-
hannover
-
hansd
-
tgrmren227
-
angiotensin-converting
-
ii-dependent
- glomerulosclerosis
- angiotensinogen
-
conscious
- losartan
-
prorenin
-
transgene-negative
-
intrarenal
-
end-organ
- valsartan
-
extra-renal
- perindopril
-
monogenetic
-
atrasentan
-
juxtaglomerular
-
prehypertensive
-
mren227
- medicine
-
bosentan
-
epoxyeicosatrienoic
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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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EC NUMBER 
COMMENTARY 
1.6.3.5
-
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RECOMMENDED NAME
GeneOntology No.
renalase
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
1,2-dihydro-beta-NAD(P) + H+ + O2 = beta-NAD(P)+ + H2O2
(1)
-
-
-
1,6-dihydro-beta-NAD(P) + H+ + O2 = beta-NAD(P)+ + H2O2
(2)
-
-
-
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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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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
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
-
renalase degrades catecholamines contributing to blood pressure control
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 protects the cardiomyocytes of Sprague-Dawley rats against ischemia and reperfusion injury by reducing myocardial cell necrosis and apoptosis
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
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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-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-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 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 SUBSTRATES
NATURAL PRODUCTS
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
Q5VYX0
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
Q48MT7
-
-
-
?
1,2-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
Q48MT7
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
Q48MT7
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
Q48MT7
-
-
-
?
1,2-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
Q48MT7
-
-
-
?
1,6-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
-
-
-
-
?
1,6-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
Q48MT7
-
-
-
?
1,6-dihydro-beta-NADH + H+ + O2
beta-NAD+ + H2O2
Q48MT7
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
-
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
Q48MT7
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
Q48MT7
-
-
-
?
1,6-dihydro-beta-NADPH + H+ + O2
beta-NADP+ + H2O2
Q48MT7
-
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
-
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
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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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
-
besides kidney, renalase gene expression is detectable in the heart, skeletal muscle, and the small intestine
substantial expression spermatogenic cells of testis. Expression increases in testes and ovaries as mice develop
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
-
besides kidney, renalase gene expression is detectable in the heart, skeletal muscle, and the small intestine
-
enzyme is secreted into the blood by the kidney. Gene expression is highest in the kidney
-
besides kidney, renalase gene expression is detectable in the heart, skeletal muscle, and the small intestine
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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PDB
SCOP
CATH
ORGANISM
UNIPROT
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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SUBUNITS
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
-
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
-
plasma concentration of renalase is markedly reduced in patients with end-stage renal disease, as compared with healthy subjects
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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LINKS TO OTHER DATABASES (specific for EC-Number 1.6.3.5)
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