Dimethylargininase
Encyclopedia
In the field of enzymology, a dimethylargininase also known as a dimethylarginine dimethylaminohydrolase (DDAH) is an enzyme
that catalyzes
the chemical reaction
:
Thus, the two substrates
of this enzyme are N-omega,N-omega'-methyl-L-arginine
and H2O
, whereas its two products
are dimethylamine
and L-citrulline.
ian cells
. Two isoforms exist, DDAH I and DDAH II, with some differences in tissue distribution of the two isoforms). The enzyme degrades methylarginine
s, specifically asymmetric dimethylarginine
(ADMA) and NG-monomethyl-L-arginine (MMA).
. As such, DDAH is important in removing methylarginines, generated by protein degradation, from accumulating and inhibiting the generation of nitric oxide.
(NO) synthesis and causing vasoconstriction
. An impairment of DDAH activity appears to be involved in the elevation of plasma ADMA, and impairment of vascular relaxation observed in humans with cardiovascular disease
or risk factors (such as hypercholesterolemia
, diabetes mellitus
, and insulin resistance
). The activity of DDAH is impaired by oxidative stress
, permitting ADMA to accumulate. A wide range of pathologic stimuli induce endothelial oxidative stress such as oxidized LDL-cholesterol, inflammatory
cytokines, hyperhomocysteinemia
, hyperglycemia
and infectious agents. Each of these insults attenuates DDAH activity in vitro and in vivo. The attenuation of DDAH allows ADMA to accumulate, and to block NO synthesis. The adverse effect of these stimuli can be reversed in vitro by antioxidants, which preserve the activity of DDAH.
The sensitivity of DDAH to oxidative stress is conferred by a critical sulfhydryl in the active site
of the enzyme that is required for the metabolism
of ADMA. This sulfhydryl can also be reversibly inhibited by NO in an elegant form of negative feedback
. Homocysteine
(a putative cardiovascular risk factor) mounts an oxidative attack on DDAH to form a mixed disulfide
, inactivating the enzyme. By oxidizing a sulfhydryl moiety
critical for DDAH activity, homocysteine and other risk factors cause ADMA to accumulate and to suppress nitric oxide synthase
(NOS) activity.
The critical role of DDAH activity in regulating NO synthesis in vivo was demonstrated using a transgenic DDAH mouse
. In this animal, the activity of DDAH is increased, and plasma
ADMA levels are reduced by 50%. The reduction in plasma ADMA is associated with a significant increase in NOS activity, as plasma and urinary
nitrate
levels are doubled. The increase in NOS activity translates into a 15mmHg reduction in systolic
blood pressure
in the transgenic mouse. This study provides evidence for the importance of DDAH activity and plasma ADMA levels in the regulation of NO synthesis. Subsequent studies have shown that DDAH transgenic animals also manifest improvements in endothelial regeneration
and angiogenesis
, and reduced vascular obstructive disease, in association with the reduced plasma levels of ADMA. These findings are consistent with evidence from a number of groups that nitric oxide plays a critical role in vascular regeneration. By contrast, elevations in ADMA impair angiogenesis. These insights into the role of DDAH in degrading endogenous inhibitors of NOS, and thereby maintaining vascular NO production, may have important implications in vascular health and therapy for cardiovascular disease.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyzes
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
the chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
:
- N-omega,N-omega'-methyl-L-arginine + H2O
dimethylamine + L-citrulline
Thus, the two substrates
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
of this enzyme are N-omega,N-omega'-methyl-L-arginine
Asymmetric dimethylarginine
Asymmetric dimethylarginine is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid...
and H2O
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, whereas its two products
Product (chemistry)
Product are formed during chemical reactions as reagents are consumed. Products have lower energy than the reagents and are produced during the reaction according to the second law of thermodynamics. The released energy comes from changes in chemical bonds between atoms in reagent molecules and...
are dimethylamine
Dimethylamine
Dimethylamine is an organic compound with the formula 2NH. This secondary amine is a colorless, flammable liquified gas with an ammonia-like odor. Dimethylamine is generally encountered as a solution in water at concentrations up to around 40%...
and L-citrulline.
Isozymes
Dimethylarginine dimethylaminohydrolase is an enzyme found in all mammalMammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. Two isoforms exist, DDAH I and DDAH II, with some differences in tissue distribution of the two isoforms). The enzyme degrades methylarginine
Methylarginine
N-Methylarginine is an inhibitor of nitric oxide synthase. Chemically, it is a methyl derivative of the amino acid arginine. It is used as a biochemical tool in the study of physiological role of nitric oxide....
s, specifically asymmetric dimethylarginine
Asymmetric dimethylarginine
Asymmetric dimethylarginine is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid...
(ADMA) and NG-monomethyl-L-arginine (MMA).
Function
The methylarginines ADMA and MMA inhibit the production of nitric oxide synthaseNitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
. As such, DDAH is important in removing methylarginines, generated by protein degradation, from accumulating and inhibiting the generation of nitric oxide.
Clinical significance
Inhibition of DDAH activity causes methylarginines to accumulate, blocking nitric oxideNitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO) synthesis and causing vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
. An impairment of DDAH activity appears to be involved in the elevation of plasma ADMA, and impairment of vascular relaxation observed in humans with cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
or risk factors (such as hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
, diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, and insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
). The activity of DDAH is impaired by oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, permitting ADMA to accumulate. A wide range of pathologic stimuli induce endothelial oxidative stress such as oxidized LDL-cholesterol, inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
cytokines, hyperhomocysteinemia
Hyperhomocysteinemia
Hyperhomocysteinemia or hyperhomocysteinaemia is a medical condition characterized by an abnormally large level of homocysteine in the blood....
, hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
and infectious agents. Each of these insults attenuates DDAH activity in vitro and in vivo. The attenuation of DDAH allows ADMA to accumulate, and to block NO synthesis. The adverse effect of these stimuli can be reversed in vitro by antioxidants, which preserve the activity of DDAH.
The sensitivity of DDAH to oxidative stress is conferred by a critical sulfhydryl in the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
of the enzyme that is required for the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of ADMA. This sulfhydryl can also be reversibly inhibited by NO in an elegant form of negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
. Homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
(a putative cardiovascular risk factor) mounts an oxidative attack on DDAH to form a mixed disulfide
Disulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....
, inactivating the enzyme. By oxidizing a sulfhydryl moiety
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
critical for DDAH activity, homocysteine and other risk factors cause ADMA to accumulate and to suppress nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
(NOS) activity.
The critical role of DDAH activity in regulating NO synthesis in vivo was demonstrated using a transgenic DDAH mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
. In this animal, the activity of DDAH is increased, and plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
ADMA levels are reduced by 50%. The reduction in plasma ADMA is associated with a significant increase in NOS activity, as plasma and urinary
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
nitrate
Nitrate
The nitrate ion is a polyatomic ion with the molecular formula NO and a molecular mass of 62.0049 g/mol. It is the conjugate base of nitric acid, consisting of one central nitrogen atom surrounded by three identically-bonded oxygen atoms in a trigonal planar arrangement. The nitrate ion carries a...
levels are doubled. The increase in NOS activity translates into a 15mmHg reduction in systolic
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
in the transgenic mouse. This study provides evidence for the importance of DDAH activity and plasma ADMA levels in the regulation of NO synthesis. Subsequent studies have shown that DDAH transgenic animals also manifest improvements in endothelial regeneration
Regeneration (biology)
In biology, regeneration is the process of renewal, restoration, and growth that makes genomes, cells, organs, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of regeneration, from bacteria to humans. At its most...
and angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, and reduced vascular obstructive disease, in association with the reduced plasma levels of ADMA. These findings are consistent with evidence from a number of groups that nitric oxide plays a critical role in vascular regeneration. By contrast, elevations in ADMA impair angiogenesis. These insights into the role of DDAH in degrading endogenous inhibitors of NOS, and thereby maintaining vascular NO production, may have important implications in vascular health and therapy for cardiovascular disease.