Arginase
Encyclopedia
Arginase is a manganese
-containing enzyme
. The reaction catalyzed by this enzyme is: arginine
+ H2O
→ ornithine
+ urea
. It is the final enzyme
of the urea cycle
.
family of enzymes.
Arginase catalyzes the fifth and final step in the urea cycle
, a series of biochemical reactions in mammals during which the body disposes of harmful ammonia
. Specifically, arginase converts L-arginine
into L-ornithine
and urea. In most mammals, two isozymes of this enzyme exist; the first, Arginase I, functions in the urea cycle, and is located primarily in the cytoplasm of the liver. The second isozyme, Arginase II, has been implicated in the regulation of the arginine/ornithine concentrations in the cell. It is located in mitochondria of several tissues in the body, with most abundance in the kidney and prostate. It may be found at lower levels in macrophages, lactating mammary glands, and brain. The second isozyme may be found in the absence of other urea cycle enzymes. Arginase consists of three tetramers. The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn2+ ions coordinate with water, orientating and stabilizing the molecule and allowing water to act as a nucleophile
and attack L-arginine, hydrolyzing it into ornithine and urea.
Arginase's active site is extraordinarily specific. Modifying the substrate structure and/or stereochemistry severely lowers the kinetic activity of the enzyme. This specificity occurs due to the high number of hydrogen bonds between substrate and enzyme; direct or water-facilitated hydrogen bonds exist, saturating both the four acceptor positions on the alpha carboxylate group and all three positions on the alpha amino group. N-hydroxy-L-arginine (NOHA), an intermediate of NO biosynthesis, is a moderate inhibitor of arginase. Crystal structure of its complex with the enzyme reveals that it displaces the metal-bridging hydroxide ion and bridges the binuclear manganese cluster.
Additionally, 2(S)-amino-6-boronohexonic acid (ABH) is an L-arginine analogue that also creates a tetrahedral intermediate similar to that formed in the catalysis of the natural substrate, and is a potent inhibitor of human arginase I.
in smooth muscle tissue, such as the muscle in the genitals of both men and women. The contraction and relaxation of these muscles has been attributed to NO synthase, which causes rapid relaxation of smooth muscle tissue and facilitates engorgement of tissue necessary for normal sexual response. However, since NO synthase and arginase compete for the same substrate (L-arginine), over-expressed arginase can affect NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would otherwise be available to NO synthase. In contrast, inhibiting arginase with ABH or other boronic acid inhibitors will maintain normal cellular levels of arginine, thus allowing for normal muscle relaxation and sexual response.
Recent studies have implicated arginase as a controlling factor in both male erectile function and female sexual arousal, and is therefore a potential target for treatment of sexual dysfunction in both sexes. Additionally, supplementing the diet with additional L-arginine will decrease the amount of competition between arginase and NO synthase by providing extra substrate for each enzyme.
typically refers to decreased function of arginase I, the liver isoform of arginase. This deficiency is commonly referred to as hyperargininemia or arginemia. The disorder is hereditary and autosomal recessive. It is characterized by lowered activity of arginase in hepatic cells. Additionally, the disorder is considered to be the rarest of the heritable defects in ureagenesis. Unlike other urea cycle disorders, ureagenesis still persists in subjects with arginase deficiency. A proposed reason for the continuation of arginase function is suggested by increased activity of arginase II in the kidneys of subjects with arginase I deficiency. Researchers believe that buildup of arginine triggers increased expression of arginase II. The enzymes in the kidney will then catalyze ureagenesis, compensating somewhat for a decrease in arginase I activity in the liver. Due to this alternate method of removing excess arginine
and ammonia from the bloodstream, subjects with arginase deficiency tend to have longer lifespans than those who have other urea cycle defects.
Symptoms of the disorder
include neurological impairment, dementia
, retardation of growth, and hyperammonemia. While some symptoms of the disease can be controlled via dietary restrictions and pharmaceutical developments, no cure or completely effective therapy currently exists.
Manganese
Manganese is a chemical element, designated by the symbol Mn. It has the atomic number 25. It is found as a free element in nature , and in many minerals...
-containing enzyme
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...
. The reaction catalyzed by this enzyme is: arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
+ 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...
→ ornithine
Ornithine
Ornithine is an amino acid that plays a role in the urea cycle.-Role in urea cycle:L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Therefore, ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen....
+ urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
. It is the final enzyme
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...
of the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
.
Structure and function
Arginase belong to the ureohydrolaseUreohydrolase
A ureohydrolase is a type of hydrolase enzyme.The ureohydrolase superfamily includes arginase , agmatinase , formiminoglutamase and proclavaminate amidinohydrolase...
family of enzymes.
Arginase catalyzes the fifth and final step in the urea cycle
Urea cycle
The urea cycle is a cycle of biochemical reactions occurring in many animals that produces urea from ammonia . This cycle was the first metabolic cycle discovered , five years before the discovery of the TCA cycle...
, a series of biochemical reactions in mammals during which the body disposes of harmful ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
. Specifically, arginase converts L-arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
into L-ornithine
Ornithine
Ornithine is an amino acid that plays a role in the urea cycle.-Role in urea cycle:L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Therefore, ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen....
and urea. In most mammals, two isozymes of this enzyme exist; the first, Arginase I, functions in the urea cycle, and is located primarily in the cytoplasm of the liver. The second isozyme, Arginase II, has been implicated in the regulation of the arginine/ornithine concentrations in the cell. It is located in mitochondria of several tissues in the body, with most abundance in the kidney and prostate. It may be found at lower levels in macrophages, lactating mammary glands, and brain. The second isozyme may be found in the absence of other urea cycle enzymes. Arginase consists of three tetramers. The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn2+ ions coordinate with water, orientating and stabilizing the molecule and allowing water to act as a nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
and attack L-arginine, hydrolyzing it into ornithine and urea.
Mechanism
The active site holds L-arginine in place via hydrogen bonding between the guanidinium group with Glu227. This bonding orients L-arginine for nucleophilic attack by the metal-associated hydroxide ion at the guanidinium group. This results in a tetrahedral intermediate. The manganese ions act to stabilize both the hydroxyl group in the tetrahedral intermediate, as well as the developing sp3 lone electron pair on the NH2 group as the tetrahedral intermediate is formed.Arginase's active site is extraordinarily specific. Modifying the substrate structure and/or stereochemistry severely lowers the kinetic activity of the enzyme. This specificity occurs due to the high number of hydrogen bonds between substrate and enzyme; direct or water-facilitated hydrogen bonds exist, saturating both the four acceptor positions on the alpha carboxylate group and all three positions on the alpha amino group. N-hydroxy-L-arginine (NOHA), an intermediate of NO biosynthesis, is a moderate inhibitor of arginase. Crystal structure of its complex with the enzyme reveals that it displaces the metal-bridging hydroxide ion and bridges the binuclear manganese cluster.
Additionally, 2(S)-amino-6-boronohexonic acid (ABH) is an L-arginine analogue that also creates a tetrahedral intermediate similar to that formed in the catalysis of the natural substrate, and is a potent inhibitor of human arginase I.
Role in sexual response
Arginase II is coexpressed with nitric oxide (NO) 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...
in smooth muscle tissue, such as the muscle in the genitals of both men and women. The contraction and relaxation of these muscles has been attributed to NO synthase, which causes rapid relaxation of smooth muscle tissue and facilitates engorgement of tissue necessary for normal sexual response. However, since NO synthase and arginase compete for the same substrate (L-arginine), over-expressed arginase can affect NO synthase activity and NO-dependent smooth muscle relaxation by depleting the substrate pool of L-arginine that would otherwise be available to NO synthase. In contrast, inhibiting arginase with ABH or other boronic acid inhibitors will maintain normal cellular levels of arginine, thus allowing for normal muscle relaxation and sexual response.
Recent studies have implicated arginase as a controlling factor in both male erectile function and female sexual arousal, and is therefore a potential target for treatment of sexual dysfunction in both sexes. Additionally, supplementing the diet with additional L-arginine will decrease the amount of competition between arginase and NO synthase by providing extra substrate for each enzyme.
Pathology
Arginase deficiencyDeficiency
A deficiency is generally a lack of something. It may also refer to:*A deficient number, in mathematics, a number n for which σ A deficiency is generally a lack of something. It may also refer to:...
typically refers to decreased function of arginase I, the liver isoform of arginase. This deficiency is commonly referred to as hyperargininemia or arginemia. The disorder is hereditary and autosomal recessive. It is characterized by lowered activity of arginase in hepatic cells. Additionally, the disorder is considered to be the rarest of the heritable defects in ureagenesis. Unlike other urea cycle disorders, ureagenesis still persists in subjects with arginase deficiency. A proposed reason for the continuation of arginase function is suggested by increased activity of arginase II in the kidneys of subjects with arginase I deficiency. Researchers believe that buildup of arginine triggers increased expression of arginase II. The enzymes in the kidney will then catalyze ureagenesis, compensating somewhat for a decrease in arginase I activity in the liver. Due to this alternate method of removing excess arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
and ammonia from the bloodstream, subjects with arginase deficiency tend to have longer lifespans than those who have other urea cycle defects.
Symptoms of the disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
include neurological impairment, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, retardation of growth, and hyperammonemia. While some symptoms of the disease can be controlled via dietary restrictions and pharmaceutical developments, no cure or completely effective therapy currently exists.
External links
- GeneReviews/NIH/NCBI/UW entry on Arginase Deficiency
- Arginase family signature and profile in PROSITEPROSITEPROSITE is a protein database. It consists of entries describing the protein families, domains and functional sites as well as amino acid patterns, signatures, and profiles in them. These are manually curated by a team of the Swiss Institute of Bioinformatics and tightly integrated into Swiss-Prot...