Uridine monophosphate synthetase
Encyclopedia
Uridine monophosphate synthetase (UMPS) (orotate phosphoribosyl transferase and orotidine-5'-decarboxylase) is the enzyme
that catalyses the formation of uridine monophosphate
(UMP), an energy-carrying molecule in many important biosynthetic pathways. In humans, the gene
that codes for this enzyme is located on the long arm of chromosome
3 (3q13).
UMPS exists in various forms, depending on external conditions. In vitro, monomeric UMPS, with a sedimentation coefficient
S20,w of 3.6 will become a dimer, S20,w = 5.1 after addition of anions such as phosphate. In the presence of OMP, the product of the OPRTase, the dimer changes to a faster sedimenting form S20,w 5.6. These separate conformational forms display different enzymatic activities, with the UMP synthase monomer displaying low decarboxylase activity, and only the 5.6 S dimer exhibiting full decarboxylase activity.
It is believed that the two separate catalytic sites fused into a single protein to stabilize its monomeric form. The covalent union in UMPS stabilizes the domains containing the respective catalytic centers, improving its activity in multicellular organisms where concentrations tend to be 1/10th of the separate counterparts in prokaryotes. Other microorganisms with separated enzymes must retain higher concentrations to keep their enzymes in its more active dimeric form.
.
Deficiency of this enzyme is an inherited autosomal recessive trait in Holstein cattle, and it will cause death before birth.
Deficiency of the enzyme can be studied in the model organism Caenorhabditis elegans. The rad-6 strain has a premature stop codon eliminating the orotidine 5’-decarboxylase domain of the protein; this domain does not occur in any other proteins encoded by the genome. The strain has a pleiotropic phenotype including reduced viability and fertility, slow growth and radiation sensitivity.
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 catalyses the formation of uridine monophosphate
Uridine monophosphate
Uridine monophosphate, also known as 5'-uridylic acid and abbreviated UMP, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside uridine...
(UMP), an energy-carrying molecule in many important biosynthetic pathways. In humans, the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that codes for this enzyme is located on the long arm of chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
3 (3q13).
Structure and Function
This bifunctional enzyme has two main domains, an orotate phosphoribosyltransferase (OPRTase) subunit and an orotidine-5’-phosphate decarboxylase (ODCase) subunit. These two sites catalyze the last two steps of the de novo uridine monophosphate (UMP) biosynthetic pathway. After addition of ribose-P to orotate by OPRTase to form orotidine-5’-monophosphate (OMP), OMP is decarboxylated to form uridine monophosphate by ODCase. In microorganisms, these two domains are separate proteins, but in multicellular eukaryotes, the two catalytic sites are expressed on a single protein, uridine monophosphate synthetase.UMPS exists in various forms, depending on external conditions. In vitro, monomeric UMPS, with a sedimentation coefficient
Sedimentation coefficient
The sedimentation coefficient s of a particle is used to characterize its behaviour in sedimentation processes, notably centrifugation. It is defined as the ratio of a particle's sedimentation velocity to the acceleration that is applied to it .The sedimentation speed v_t is also known as the...
S20,w of 3.6 will become a dimer, S20,w = 5.1 after addition of anions such as phosphate. In the presence of OMP, the product of the OPRTase, the dimer changes to a faster sedimenting form S20,w 5.6. These separate conformational forms display different enzymatic activities, with the UMP synthase monomer displaying low decarboxylase activity, and only the 5.6 S dimer exhibiting full decarboxylase activity.
It is believed that the two separate catalytic sites fused into a single protein to stabilize its monomeric form. The covalent union in UMPS stabilizes the domains containing the respective catalytic centers, improving its activity in multicellular organisms where concentrations tend to be 1/10th of the separate counterparts in prokaryotes. Other microorganisms with separated enzymes must retain higher concentrations to keep their enzymes in its more active dimeric form.
Regulation
UMPS is subject to complex regulation by OMP, the product of its OPRTase and the substrate for the ODCase. OMP is an allosteric activator of OMP decarboxylase activity. At low enzyme concentration and low OMP concentrations, OMP decarboxylase shows negative cooperativity, while at higher OMP concentrations, the enzyme shows positive cooperativity. However, when enzyme concentrations are higher, these complex kinetics do not manifest. Orotate PRTase activity is activated by low concentrations of OMP, phosphate, and ADP.Clinical significance
A UMP synthetase deficiency can result in a metabolic disorder called orotic aciduriaOrotic aciduria
-Signs and symptoms:In addition to the characteristic excessive orotic acid in the urine, patients typically have megaloblastic anemia which cannot be cured by administration of vitamin B12 or folic acid....
.
Deficiency of this enzyme is an inherited autosomal recessive trait in Holstein cattle, and it will cause death before birth.
Deficiency of the enzyme can be studied in the model organism Caenorhabditis elegans. The rad-6 strain has a premature stop codon eliminating the orotidine 5’-decarboxylase domain of the protein; this domain does not occur in any other proteins encoded by the genome. The strain has a pleiotropic phenotype including reduced viability and fertility, slow growth and radiation sensitivity.