| RNLS | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | RNLS , C10orf59, RENALASE, renalase, FAD-dependent amine oxidase, renalase, FAD dependent amine oxidase | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 609360 MGI: 1915045 HomoloGene: 41254 GeneCards: RNLS | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Renalase, FAD-dependent amine oxidase is an enzyme that in humans is encoded by the RNLS gene. Renalase is a flavin adenine dinucleotide-dependent amine oxidase that is secreted into the blood from the kidney. [5]
The gene encoding this protein is called RNLS (also known as C10orf59 or FLJ11218). [5] The renalase gene has 9 exons spanning approximately 311,000 bp and resides on chromosome 10 at q23.33. [6]
The renalase protein consists of a putative secretory signal peptide (SignalP score of 0.4), a flavin adenine dinucleotide (FAD)-binding region, and an oxidase domain. At least four alternative splicing isoforms have been identified in humans (hRenalase1 to hRenalase4). Only hRenalase1 is detected in human blood samples, which means that hRenalase2 to 4 probably have different functions than hRenalase1. [7]
Analysis of the primary structure of renalase shows that it is an FAD-dependent oxidase. The X-ray crystal structure of hRenalase1 reveals structural similarity between renalase and p-hydroxybenzoate hydroxylase. [8]
Renalase has been claimed to degrade catecholamines like adrenaline (epinephrine) and noradrenaline (norepinephrine) in the blood circulation. [7] Dr. Gary Desir's laboratory at Yale School of Medicine discovered and named renalase in 2005 [6] suggest that the human kidney releases this protein into the bloodstream to regulate blood pressure (in addition to other possible, as yet undiscovered, functions). [7]
Whether renalase actually oxidizes catecholamine substrates has been widely disputed. [9] [10] The primary evidence for catecholamine oxidation is the detection of H2O2, however catecholamines emanate H2O2 in the presence of O2 in a natural decomposition reaction. In 2013, renalase was claimed to oxidize α-NADH (the normal form of NADH is the β anomer) to β-NAD+, with concomitant reduction of O2 (dioxygen) to H2O2 (hydrogen peroxide). [11] This reaction was proposed to repair aberrant NADH and NADPH forms that are not accepted as cofactors by most nicotinamide-dependent oxidoreductase enzymes.
It transpired that α-NAD(P)H molecules are not substrates for renalase; instead 6-dihydroNAD (6DHNAD) was identified as the substrate, a molecule with highly similar spectrophotometric characteristics and equilibrium concentrations as those reported for α-NAD(P)H. [12] 6DHNAD is an isomeric form of β-NADH that carries the hydride in the 6-position of the nicotinamide base as opposed to the metabolically active 4-position. This form of NAD is one of three products that are formed from non-enzymatic reduction of β-NAD+ in addition to 4-dihydroNAD (β-NADH), 2-dihydroNAD (2DHNAD). Both 2DHNAD and 6DHNAD were shown to be substrates for renalase. These molecules react rapidly to reduce the enzyme's flavin cofactor forming β-NAD+. The renalase flavin then delivers the electrons harvested to O2 (dioxygen) forming H2O2 (hydrogen peroxide), completing the catalytic cycle. It was shown that both 6DHNAD and 2DHNAD are tight binding inhibitors of specific primary metabolism dehydrogenases, thereby defining a clear metabolic function for renalase in the alleviation of this inhibition.
Extracellular renalase functions as a survival and growth factor, independent of its enzymatic activity. [13] Either naturally folded renalase or a 20 amino acid renalase peptide can activate the phosphoinositide 3-kinase (PI3K)and the mitogen-activated protein kinase (MAPK) pathways in a manner that protects cells against apoptosis.
Renalase isolated in native form, that is, without refolding steps, catalyzes the oxidation of 6DHNAD(P) or 2DHNAD(P), the isomeric forms of β-NAD(P)H . [11] In contrast to clear evidence for catalysis of this activity, the native renalase used in these experiments did not catalyze the conversion of the catecholamine epinephrine to adrenochrome. [11]
Renalase is secreted in plasma, and functions as an anti-apoptotic survival factor. The Plasma membrane Ca2+ ATPase PMCA4b is a putative receptor for extracellular renalase. [14] The binding of renalase to PMCA4b stimulates calcium efflux with subsequent activation of the PI3K and MAPK pathways, increased expression of the anti-apoptotic factor Bcl-2, and decreased caspase3-mediated apoptosis. Administration of recombinant renalase protects against acute kidney injury (AKI), and against cardiac ischemia in animal models.
Renalase levels are markedly reduced in patients with severe chronic kidney disease (end-stage renal disease, ESRD). Since hormones like erythropoietin are secreted less in ESRD, renalase may also be a kidney hormone, although it is also expressed in heart muscle, skeletal muscle and liver cells in humans, and in mouse testicles. [7] [15]
Renalase has been controversially proposed to degrade catecholamines, which are hormones involved in the acute stress (fight-or-flight) response. Injection of renalase in rodents transiently decreases blood pressure, heart rate, heart muscle contractility, and blood vessel resistance. [6] Under normal conditions, renalase is present but inactive in the bloodstream. When catecholamines are released into the bloodstream however, renalase activity increases about tenfold within 30 seconds, and remains high for an hour or longer. Activation of circulating renalase is probably responsible for early activation, while secretion into the bloodstream occurs after 15 minutes. [16]
polymorphisms in the renalase gene is a risk factor for essential hypertension. [17]
Single nucleotide polymorphisms in the renalase gene are associated with type 1 diabetes. A genome-wide association study and meta-analysis found that approximately 42 loci affect the risk of diabetes [18] The data confirmed linkage with most of the 24 previously identified loci, and identified 27 novel loci. The strongest evidence of association among these novel regions was achieved for the renalase gene.
In mice, hearts exposed to oxygen shortage (ischemia), myocardial infarction size was decreased and heart function better preserved when renalase was administered. [19] Renalase knock-out mice are also more sensitive to damage to the heart muscle. [7] Renalase expression in the heart is also decreased in the rat model of end-stage renal disease. The scientists who discovered renalase believe that it might explain some of the susceptibility to heart disease among patients with chronic kidney disease. [7]
Using small inhibitory RNAs or knock-out mice, the consequences of loss of renalase function have been studied. These include raised blood pressure (hypertension), increased heart rate (tachycardia), increased blood vessel resistance (vasoconstriction) and an increased catecholamine response. [20] [21]
In a rat model of chronic kidney disease (in which 85% of kidney tissue is surgically removed), renalase deficiency and defective renalase activation develops 2–3 weeks after surgery. [16]
A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as forward reactions, and in some cases this has physiological significance: for example, alcohol dehydrogenase catalyzes the oxidation of ethanol to acetaldehyde in animals, but in yeast it catalyzes the production of ethanol from acetaldehyde.
The glucose oxidase enzyme also known as notatin is an oxidoreductase that catalyses the oxidation of glucose to hydrogen peroxide and D-glucono-δ-lactone. This enzyme is produced by certain species of fungi and insects and displays antibacterial activity when oxygen and glucose are present.
In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which may be in the form of FAD or flavin mononucleotide (FMN). Many flavoproteins are known: components of the succinate dehydrogenase complex, α-ketoglutarate dehydrogenase, and a component of the pyruvate dehydrogenase complex.
Any enzyme system that includes cytochrome P450 protein or domain can be called a P450-containing system.
Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α) and C3 (β) of the acyl-CoA thioester substrate. Flavin adenine dinucleotide (FAD) is a required co-factor in addition to the presence of an active site glutamate in order for the enzyme to function.
D-amino acid oxidase is an enzyme with the function on a molecular level to oxidize D-amino acids to the corresponding α-keto acids, producing ammonia and hydrogen peroxide. This results in a number of physiological effects in various systems, most notably the brain. The enzyme is most active toward neutral D-amino acids, and not active toward acidic D-amino acids. One of its most important targets in mammals is D-Serine in the central nervous system. By targeting this and other D-amino acids in vertebrates, DAAO is important in detoxification. The role in microorganisms is slightly different, breaking down D-amino acids to generate energy.
Dihydrolipoamide dehydrogenase (DLD), also known as dihydrolipoyl dehydrogenase, mitochondrial, is an enzyme that in humans is encoded by the DLD gene. DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide.
The glycerol-3-phosphate shuttle is a mechanism used in skeletal muscle and the brain that regenerates NAD+ from NADH, a by-product of glycolysis. The NADH generated during glycolysis is found in the cytoplasm and must be transported into the mitochondria to enter the oxidative phosphorylation pathway. However, the inner mitochondrial membrane is impermeable to NADH and NAD+ and does not contain a transport system for these electron carriers. Either the glycerol-3-phosphate shuttle pathway or the malate-aspartate shuttle pathway, depending on the tissue of the organism, must be taken to transport electrons from cytoplasmic NADH into the mitochondria. The shuttle consists of the sequential activity of two proteins; Cytoplasmic glycerol-3-phosphate dehydrogenase (cGPD) transfers an electron pair from NADH to dihydroxyacetone phosphate (DHAP), forming glycerol-3-phosphate (G3P) and regenerating NAD+ needed to generate energy via glycolysis. The other protein, mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) catalyzes the oxidation of G3P by FAD, regenerating DHAP in the cytosol and forming FADH2 in the mitochondrial matrix. In mammals, its activity in transporting reducing equivalents across the mitochondrial membrane is considered secondary to the malate-aspartate shuttle.
Glycerol-3-phosphate dehydrogenase (GPDH) is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate to sn-glycerol 3-phosphate.
In enzymology, a malate oxidase (EC 1.1.3.3) is an enzyme that catalyzes the chemical reaction
In enzymology, a ferric-chelate reductase (EC 1.16.1.7) is an enzyme that catalyzes the chemical reaction
In enzymology, a NADH peroxidase (EC 1.11.1.1) is an enzyme that catalyzes the chemical reaction
NADPH oxidase 4 is an enzyme that in humans is encoded by the NOX4 gene, and is a member of the NOX family of NADPH oxidases.
Endothelial PAS domain-containing protein 1 is a protein that is encoded by the EPAS1 gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration. The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.
Hydroxycarboxylic acid receptor 2 (HCA2), also known as GPR109A and niacin receptor 1 (NIACR1), is a protein which in humans is encoded (its formation is directed) by the HCAR2 gene and in rodents by the Hcar2 gene. The human HCAR2 gene is located on the long (i.e., "q") arm of chromosome 12 at position 24.31 (notated as 12q24.31). Like the two other hydroxycarboxylic acid receptors, HCA1 and HCA3, HCA2 is a G protein-coupled receptor (GPCR) located on the surface membrane of cells. HCA2 binds and thereby is activated by D-β-hydroxybutyric acid (hereafter termed β-hydroxybutyric acid), butyric acid, and niacin (also known as nicotinic acid). β-Hydroxybutyric and butyric acids are regarded as the endogenous agents that activate HCA2. Under normal conditions, niacin's blood levels are too low to do so: it is given as a drug in high doses in order to reach levels that activate HCA2.
Apoptosis-inducing factor 2 (AIFM2), also known as ferroptosis suppressor protein 1 (FSP1), apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the AIFM2 gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10.
Iodotyrosine deiodinase, also known as iodotyrosine dehalogenase 1, is a type of deiodinase enzyme that scavenges iodide by removing it from iodinated tyrosine residues in the thyroid gland. These iodinated tyrosines are produced during thyroid hormone biosynthesis. The iodide that is scavenged by iodotyrosine deiodinase is necessary to again synthesize the thyroid hormones. After synthesis, the thyroid hormones circulate through the body to regulate metabolic rate, protein expression, and body temperature. Iodotyrosine deiodinase is thus necessary to keep levels of both iodide and thyroid hormones in balance.
L-ornithine N5 monooxygenase (EC 1.14.13.195 or EC 1.14.13.196) is an enzyme which catalyzes one of the following chemical reactions:
L-ornithine + NADPH + O2 N(5)-hydroxy-L-ornithine + NADP+ + H2O L-ornithine + NAD(P)H + O2 N(5)-hydroxy-L-ornithine + NAD(P)+ + H2O
Cytochrome P450 aromatic O-demethylase is a bacterial enzyme that catalyzes the demethylation of lignin and various lignols. The net reaction follows the following stoichiometry, illustrated with a generic methoxy arene:
Gary V. Desir is a physician, researcher and medical practitioner who was appointed as the vice provost for faculty development and diversity at Yale University in March 2020. Desir is also the chair of the department of internal medicine at Yale School of Medicine, and was formerly the chair of the Yale Medicine Board. His areas of specialization include nephrology and molecular physiology, the latter specifically about potassium channels. His notable research work includes discovery of the kidney protein renalase.
