How to Control NO Production in Cells: Nω,Nω‐Dimethyl‐<scp>L</scp>‐Arginine Dimethylaminohydrolase as a Novel Drug Target

Knipp, Markus

doi:10.1002/cbic.200500527

Cited by 28 publications

(19 citation statements)

References 179 publications

(172 reference statements)

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“…Redox modification of a sulfhydryl group in the catalytic region of the active site of DDAH could confer reversible sensitivity of the enzyme to oxidative stress (78,167). For example, homocysteine oxidizes a sulfhydryl group in DDAH to form a mixed disulfide, which inactivates the enzyme (167).…”

Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

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Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

287

301

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Palm F, Onozato ML, Luo Z, Wilcox CS. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol 293: H3227-H3245, 2007. First published October 12, 2007; doi:10.1152 doi:10. /ajpheart.00998.2007 )-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH ϩ/Ϫ mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation in kidneys reduces the expression of DDAH-1 but increases the expression of DDAH-2. This rapidly evolving evidence of isoform-specific distribution and regulation of DDAH expression in the kidney and blood vessels provides potential mechanisms for nephron site-specific regulation of NO production. In this review, the recent advances in the regulation and function of DDAH enzymes, their roles in the regulation of NO generation, and their possible contribution to endothelial dysfunction in patients with cardiovascular and kidney diseases are discussed. nitric oxide synthase; hypertension; diabetes mellitus; chronic kidney disease; asymmetric dimethylarginineis an endogenous methylated amino acid that inhibits the constitutive endothelial (e) or type III and neuronal (n) or type I isoforms of nitric oxide (NO) synthase (NOS) (49,91,103,199). It is a less potent inhibitor of the inducible (i) or type II NOS isoform (41,191,213). Proteins are subject to methylation of arginine residues by protein arginine methyltransferase (PRMT). S-adenosylmethionine, which is synthesized from methionine and ATP, serves as the methyl donor and, in the process, is converted to S-adenosylhomocysteine, which itself can be hydrolyzed to homocysteine. Remethylation of homocysteine in the "remethylation pathway" regenerates methionine (14,179). ADMA is released by protein hydrolysis and exported from the cell and taken up by other cells via system y ϩ carriers of the cationic amino acid (CAT) family (14,196,212). ADMA is eliminated both by renal excretion and metabolic degradation. Its metabolism is facilitated by dimethylarginine dimethylaminohydrolases (DDAHs), which are expressed as type 1 and 2 isoforms. Recent studies have shown differential sites of expression of DDAH-1 and -2 in blo...

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Section: Sites Of Ddah Expression and Functionmentioning

confidence: 99%

“…Readers are referred to recent reviews for further information on the cardiovascular and renal actions of NO (50, 86,87,151,154,195,216,217,218) and ADMA (14,18,21,34,91,99,189,192,193,196,197,234,235). The chemistry of DDAH has been reviewed recently (78).…”

mentioning

confidence: 99%

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Palm

Onozato²,

Luo³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

287

301

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“…Much of the pathway for inhibition of NO synthesis by ADMA is known. This endogenously produced arginine analog can be transported by the y ϩ cationic amino acid transporter (10) and is known to be an inhibitor of all three NO synthase isoforms (11). Pathological accumulation of ADMA has been proposed as a ubiquitous mechanism for endothelial dysfunction and has even been called an "über marker" for adverse cardiovascular conditions (12).…”

mentioning

confidence: 99%

“…Pathological accumulation of ADMA has been proposed as a ubiquitous mechanism for endothelial dysfunction and has even been called an "über marker" for adverse cardiovascular conditions (12). The plasma concentrations of ADMA are partially controlled by one or both isozymes of the enzyme dimethylarginine dimethylaminohydrolase (DDAH-1 and DDAH-2), which hydrolyze ADMA (Scheme 1, structure 1) to the non-inhibitory (or less-inhibitory) products citrulline (Scheme 1, structure 2) and dimethylamine (Scheme 1, structure 3) (11). The systemic inhibition of DDAH activity by small molecules (13) and the transgenic overexpression of the DDAH-1 isoform (14) result in respective increases or decreases in blood pressure, as predicted, highlighting the importance of DDAH in controlling ADMA, NO, and vasodilation in vivo (15).…”

mentioning

confidence: 99%

“…Elevated tHcy levels have been proposed to increase plasma ADMA concentrations by inhibiting DDAH activity through a decrease in expression levels or through direct inhibition by Hcy, by associated reactive oxygen or nitrogen species, or by zinc ions released during oxidative stress (6,9,11). Here we report the heterologous expression, purification and characterization of the recombinant human DDAH-1 isoform and quantify its sensitivity to inhibition by L-homocysteine (Hcy), hydrogen peroxide (H 2 O 2 ), and S-nitroso-L-homocysteine (HcyNO).…”

mentioning

confidence: 99%

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Inhibition of Human Dimethylarginine Dimethylaminohydrolase-1 by S-Nitroso-L-homocysteine and Hydrogen Peroxide

Lin¹,

Fast²

2007

Journal of Biological Chemistry

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The plasma concentrations of two cardiovascular risk factors, total homocysteine (tHcy) and asymmetric dimethylarginine (ADMA), correlate with decreased levels of endothelium-derived nitric oxide and subsequent endothelial dysfunction. Homocysteine has been proposed to inhibit the catabolic enzyme of ADMA, dimethylarginine dimethylaminohydrolase (DDAH), but the mechanism of this inhibition has not been fully elucidated. Here, the human DDAH isoform-1 (DDAH-1) is heterologously expressed and purified. Cys 274 and His 173 are identified as active site residues and the pH rate dependence is described. Because oxidation of the active site Cys has been suggested as an inhibitory mechanism in patients with hyperhomocysteinemia, the sensitivity of DDAH-1 to inhibition by L-homocysteine, H 2 O 2 , and S-nitroso-L-homocysteine is quantified. DDAH-1 is surprisingly insensitive to inactivation by the powerful oxidant, H 2 O 2 (0.088 M ؊1 s ؊1 ), possibly because of a substrate-assisted mechanism that allows the active site cysteine to remain predominantly protonated and less reactive in the resting enzyme. In contrast, DDAH-1 is sensitive to inactivation by S-nitroso-L-homocysteine (3.79 M ؊1 s ؊1 ). This work illustrates how a particular catalytic mechanism can result in selective redox regulation and has possible implications for hyperhomocysteinemia.Endothelium-derived nitric oxide (NO) regulates vasorelaxation as well as other vascular functions (1). Endothelial dysfunction is observed in many conditions including hypercholesterolemia, hypertension, diabetes, hyperhomocysteinemia, chronic renal failure, smoking, and aging, and often correlates with a decrease in endothelium-derived NO and the associated vasodilation (2). Elevated plasma concentrations of at least two cardiovascular risk factors, asymmetric N ,N -dimethyl-L-arginine (ADMA) 2 and total homocysteine (tHcy), are known to be associated with endothelial dysfunction (3-5). These two markers have been proposed to be mechanistically linked and to mediate at least part of the pathobiology of patients with hyperhomocysteinemia (6 -9). Much of the pathway for inhibition of NO synthesis by ADMA is known. This endogenously produced arginine analog can be transported by the y ϩ cationic amino acid transporter (10) and is known to be an inhibitor of all three NO synthase isoforms (11). Pathological accumulation of ADMA has been proposed as a ubiquitous mechanism for endothelial dysfunction and has even been called an "über marker" for adverse cardiovascular conditions (12). The plasma concentrations of ADMA are partially controlled by one or both isozymes of the enzyme dimethylarginine dimethylaminohydrolase (DDAH-1 and DDAH-2), which hydrolyze ADMA (Scheme 1, structure 1) to the non-inhibitory (or less-inhibitory) products citrulline (Scheme 1, structure 2) and dimethylamine (Scheme 1, structure 3) (11). The systemic inhibition of DDAH activity by small molecules (13) and the transgenic overexpression of the DDAH-1 isoform (14) result in respective increases or decre...

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Dimethylarginine‐Dimethylaminohydrolase‐2 (DDAH‐2) Does Not Metabolize Methylarginines

et al. 2012

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Free endogenous methylarginines, N(ω)-monomethyl-L-arginine (L-NMMA) and N(ω),N(ω')-dimethyl-L-arginine (ADMA), inhibit NO synthases (NOSs) and are metabolized by dimethylargininedimethylaminohydrolase (DDAH). A postulated metabolism has been shown several times for DDAH-1, but the involvement of DDAH-2 in the degradation of ADMA and L-NMMA is still a matter of debate. Determination of the isoform-specific DDAH protein expression profiles in various porcine tissue types shows a correlation of DDAH activity only with DDAH-1 levels. DDAH activity (measured as L-citrulline formation from the conversion of methylarginines and alternative DDAH substrates) was detected in DDAH-1-rich porcine tissue types, that is, kidney, liver, and brain, but not in DDAH-2-rich porcine fractions, that is, spleen and thyroid. Furthermore, several ex vivo studies showed DDAH activity to be important for L-citrulline formation in porcine tissue and indicated the absence of an endogenous DDAH inhibitor in porcine tissue. This study provides new insights into tissue distributions as well as substrate selectivity for both DDAH isoforms. Although DDAH-1 is known to metabolize the endogenous NOS inhibitors L-NMMA and ADMA, a physiological function for DDAH-2 has yet to be determined. Hence, determining DDAH activity by methylarginine conversion is not suitable for analyzing isoform selectivity of DDAH-1 inhibitors as postulated.

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How to Control NO Production in Cells: N^ω,N^ω‐Dimethyl‐L‐Arginine Dimethylaminohydrolase as a Novel Drug Target

Cited by 28 publications

References 179 publications

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Inhibition of Human Dimethylarginine Dimethylaminohydrolase-1 by S-Nitroso-L-homocysteine and Hydrogen Peroxide

Dimethylarginine‐Dimethylaminohydrolase‐2 (DDAH‐2) Does Not Metabolize Methylarginines

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How to Control NO Production in Cells: Nω,Nω‐Dimethyl‐L‐Arginine Dimethylaminohydrolase as a Novel Drug Target

Cited by 28 publications

References 179 publications

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems

Inhibition of Human Dimethylarginine Dimethylaminohydrolase-1 by S-Nitroso-L-homocysteine and Hydrogen Peroxide

Dimethylarginine‐Dimethylaminohydrolase‐2 (DDAH‐2) Does Not Metabolize Methylarginines

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How to Control NO Production in Cells: N^ω,N^ω‐Dimethyl‐L‐Arginine Dimethylaminohydrolase as a Novel Drug Target