guanosine monophosphate reductase | |||||||
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Identifiers | |||||||
Symbol | GMPR | ||||||
NCBI gene | 2766 | ||||||
HGNC | 4376 | ||||||
OMIM | 139265 | ||||||
RefSeq | NM_006877 | ||||||
UniProt | P36959 | ||||||
Other data | |||||||
EC number | 1.7.1.7 | ||||||
Locus | Chr. 6 p23 | ||||||
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guanosine monophosphate reductase 2 | |||||||
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Identifiers | |||||||
Symbol | GMPR2 | ||||||
NCBI gene | 51292 | ||||||
HGNC | 4377 | ||||||
OMIM | 610781 | ||||||
RefSeq | NM_016576 | ||||||
UniProt | Q9P2T1 | ||||||
Other data | |||||||
Locus | Chr. 14 q11.2 | ||||||
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GMP reductase EC 1.7.1.7 (Guanosine 5'-monophosphate oxidoreductase ) is an enzyme that catalyzes the irreversible and NADPH-dependent reductive deamination of GMP into IMP. [1]
NADPH + guanosine 5-phosphate = NADP+ + inosine 5-phosphate + NH3
By converting guanosine nucleotides to inosine nucleotides, which serve as precursors to both adenosine (A) and G nucleotides, it helps maintains intracellular balance of A and G nucleotides. [2] GMP can be broken down (catabolized) by other enzymes, but GMPR catalyzes the only recognized route for converting GMP to AMP (indirectly, through the IMP intermediate). [3] Whereas the conversion of GMP to IMP involves a single enzyme, GMPR, the conversion of IMP to GMP involves two enzymes. First, inosine monophosphate dehydrogenase (IMPDH) catalyzes the conversion of IMP to XMP; then GMP synthetase (GMPS) catalyzes the conversion of XMP to GMP. These two pathways are inversely regulated, with conditions favoring IMPDH expression decreasing GMPR expression. [3] In melanocytic cells, GMP reductase gene expression may be regulated by MITF. [4] It is activated by GTP and inhibited by xanthosine 5'-monophosphate (XMP). [5]
The amino acid sequence that makes up the GMP reductase is similar across organisms. In humans, there are hGMPR1 and hGMPR2, 2 GMP reductases that are different in their amino acid sequence (90% of the sequence is conserved) but has the same function overall. Although hGMPR1 and hGMPR2 do not have an identical amino acid sequence, they have similar kinetic properties and they both use NADPH as a coenzyme for their catalyzed reaction. [6] Aside from human erythrocytes, GMPR has been isolated from E.coli as well as rodents. [7]
A crystal structure of hGMPR2 was obtained, and the model shows that hGMPR2 is a homotetramer that consist of a mix of alpha helices and beta sheets (parallel and antiparallel). Each monomer interacts with each other at their edges, which allow for stabilization of the tetramer structure. On the surface of each monomer, there are phosphate molecules that exist without any interactions with other subunits. The monomers are listed as monomer A, B, C and D. Monomers A and B consist of 338 residues, one GMP and two sulfate ions. Monomer C is similar, consisting of 327 residues, one GMP molecule and two sulfate ions. Monomer D, however, does not contain a GMP molecule and only consist of 317 residues and two sulfate ions. The alpha helices and beta sheets comes together to form a 8-stranded barrel core, in which it contains several hydrophobic residues that allow the stabilization of the core. The structure also contains disulfide bonds between Cys68 and Cys95, which are not conserved in most GMPRs, but is proposed to be important for stabilizing the entire tetramer structure. [6]
The overall reaction consists of two steps: a deamination step, in which ammonia is released from guanosine and a covalent enzyme-GXP (E-XMP*) intermediate is formed, followed by a hydride transfer step, in which E-XMP* is reduced with a hydride from NADPH, releasing IMP. [8] Inosine monophosphate dehydrogenase (IMPDH) and GMPR have similar catalytic mechanisms but different structural dynamics. [3]
The rat version of GMPR is expressed in brown adipose tissue (BAT) when certain conditions triggers its response and it is mainly present in the kidney, as well as cardiac and skeletal muscle. One of these conditions include cold stimulation. When the organism is exposed to the cold, the GMPR RNA expression can increase to a maximum of 30 fold, allowing heat production. A hypothesis for this occurring is that the conversion of GMP to IMP potentially increase adenylosuccinate (precursor of AMP), which allows for the production of a second messenger cAMP. This messenger is important for the BAT heat production. [7]
It has been realized that GMPR and its products increases in Alzheimer's disease. The GMPR gene encodes for the protein GMPR1 (GMP reductase enzyme) that catalyzes the reaction for converting GMP to IMP. IMP can also be converted to AMP and adenosine (A). The presence of the adenosine can bind to A1/A2 receptors (important for mediation of Tau phosphorylation) which ultimately results in increased expression of Alzheimer's disease. This is because Alzheimer's disease is due to neurofilament tangles (NFT) forming inside neurons, and phosphorylation of tau is one of the reasons for why the tangles form. Activation of the adenosine receptors increases the tangling of neurofilaments so Alzheimer's disease patients' conditions will worsen. By testing for possible inhibitors of GMPR1, it can help eliminate Tau phosphorylation. [9]
GMPR is also involved in the skin cancer melanoma. For patients with melanoma, expression of GMPR becomes reduced. An important role that GMPR plays in melanoma is that it reduces Rho-GTPases and it prevents melanoma cells from forming invadopodia, breaking down the extracellular matrix, and growing as tumors. It does this by using up or essentially decreasing the amount of GTP available. This decreases the supply of guanosine available and therefore, decrease the potential of having an invasive property. By decreasing the amounts of GMPR, it increases the chance of invasion and symptoms of melanoma to occur. Therefore, GMPR is needed to suppress melanoma invasion. [10]
GMPR also plays a role in leukemia. It has been found that in the cases of promyelocytic leukemia cells being differentiate to monocytes, the expression of GMPR has increased by a lot. Therefore, the gene for GMPR can also be a potential target for the treating leukemia. [11]
Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.
Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.
A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.
In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic monomeric building blocks for RNA. Deoxyribonucleotides, formed by reducing ribonucleotides with the enzyme ribonucleotide reductase (RNR), are essential building blocks for DNA. There are several differences between DNA deoxyribonucleotides and RNA ribonucleotides. Successive nucleotides are linked together via phosphodiester bonds.
Phosphoglucomutase is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1 to the 6 position in the forward direction or the 6 to the 1 position in the reverse direction.
A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.
In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.
Inosinic acid or inosine monophosphate (IMP) is a nucleotide. Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in metabolism. It is the ribonucleotide of hypoxanthine and the first nucleotide formed during the synthesis of purine nucleotides. It can also be formed by the deamination of adenosine monophosphate by AMP deaminase. It can be hydrolysed to inosine.
AMP deaminase 1 is an enzyme that in humans is encoded by the AMPD1 gene.
A nucleotidase is a hydrolytic enzyme that catalyzes the hydrolysis of a nucleotide into a nucleoside and a phosphate.
Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.
The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.
Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.
Guanosine monophosphate synthetase, also known as GMPS is an enzyme that converts xanthosine monophosphate to guanosine monophosphate.
In enzymology, an adenosine-phosphate deaminase (EC 3.5.4.17) is an enzyme that catalyzes the chemical reaction
Inosine-5′-monophosphate dehydrogenase (IMPDH) is a purine biosynthetic enzyme that catalyzes the nicotinamide adenine dinucleotide (NAD+)-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the first committed and rate-limiting step towards the de novo biosynthesis of guanine nucleotides from IMP. IMPDH is a regulator of the intracellular guanine nucleotide pool, and is therefore important for DNA and RNA synthesis, signal transduction, energy transfer, glycoprotein synthesis, as well as other process that are involved in cellular proliferation.
Inosine-5'-monophosphate dehydrogenase 2, also known as IMP dehydrogenase 2, is an enzyme that in humans is encoded by the IMPDH2 gene.
The Purine Nucleotide Cycle is a metabolic pathway in protein metabolism requiring the amino acids aspartate and glutamate. The cycle is used to regulate the levels of adenine nucleotides, in which ammonia and fumarate are generated. AMP converts into IMP and the byproduct ammonia. IMP converts to S-AMP (adenylosuccinate), which then converts to AMP and the byproduct fumarate. The fumarate goes on to produce ATP (energy) via oxidative phosphorylation as it enters the Krebs cycle and then the electron transport chain. Lowenstein first described this pathway and outlined its importance in processes including amino acid catabolism and regulation of flux through glycolysis and the Krebs cycle.
In molecular biology, the IMPDH/GMPR family of enzymes includes IMP dehydrogenase and GMP reductase. These enzymes are involved in purine metabolism. These enzymes adopt a TIM barrel structure.
The gua operon is responsible for regulating the synthesis of guanosine mono phosphate (GMP), a purine nucleotide, from inosine monophosphate. It consists of two structural genes guaB (encodes for IMP dehydrogenase or and guaA apart from the promoter and operator region.