Uridine monophosphate synthetase

4HKP, 2EAW, 2JGY, 2P1F, 2QCC, 2QCD, 2QCE, 2QCF, 2QCG, 2QCH, 2QCL, 2QCM, 2QCN, 2V30, 2WNS, 3BGG, 3BGJ, 3BK0, 3BVJ, 3DBP, 3EWU, 3EWW, 3EWX, 3EWY, 3EWZ, 3EX1, 3EX2, 3EX3, 3EX4, 3EX6, 3G3D, 3G3M, 3L0K, 3L0N, 3MI2, 3MO7, 3MW7, 4HIB737222247ENSG00000114491ENSMUSG00000022814P11172P13439NM_000373NM_009471NM_001348087NP_000364NP_033497NP_001335016Uridine monophosphate synthase (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).2eaw: Human UMP Synthase (C-terminal Domain- Orotidine 5'-Monophosphate Decarboxylase)2jgy: THE CRYSTAL STRUCTURE OF HUMAN OROTIDINE-5'-DECARBOXYLASE DOMAIN OF HUMAN URIDINE MONOPHOSPHATE SYNTHETASE (UMPS)2p1f: Human UMP Synthase (C-terminal Domain-Orotidine 5'-Monophosphate Decarboxylase) Uridine monophosphate synthase (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). This bifunctional enzyme has two main domains, an orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) subunit and an orotidine-5’-phosphate decarboxylase (ODCase, EC 4.1.1.23) 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 synthase. 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 their more active dimeric form. Fusion events between OPRTase and ODCase, which have led to the formation of the bifunctional enzyme UMPS, have occurred distinctly in different branches of the tree of life. For one thing, even though OPRTase is found at the N-terminus and ODCase at the C-terminus in most eukaryotes (e.g., Metazoa, Amoebozoa, Plantae, and Heterolobosea), the inverted fusion, which is to say OPRTase at the C-terminus and ODCase at the N-terminus, has also been shown to exist (e.g., parasitic protists, trypanosomastids, and stramenopiles). Moreover, other eukaryotic groups, such as Fungi, conserve both enzymes as separate proteins. However important the fusion order is, the evolutionary origin of each catalytic domain in UMPS is also a matter of study. Both OPRTase and ODCase have passed through lateral gene transfer, resulting in eukaryotes' having enzymes from bacterial and eukaryotic origin. For instance, Metazoa, Amoebozoa, Plantae, and Heterolobosea have eukaryotic ODCase and OPRTase, whereas Alveolata and stramenopiles have bacterial ones. Other rearrangements are also possible, since Fungi have bacterial OPRTase and eukaryotic ODCase, whereas kinetoplastids have the inverse combination. Merging both the fusion order and evolutionary origin, organisms end up having fused UMPS where one of its catalytic domains comes from bacteria and the other from eukaryotes. The driving force for these fusion events seems to be the acquired thermal stability. Homo sapiens OPRTase and ODCase activities lower to a greater extent when heated than the fused protein does. To determine the driving force of protein association, several experiments have been performed separating both domains and changing the linker peptide that keeps them together. In Plasmodium falciparum, the OPRTase-OMPDCase complex increases the kinetic and thermal stability when compared to monofunctional enzymes. In H. sapiens, even though separate and fused domains have a similar activity, the former have a higher sensitivity to conditions promoting monomer dissociation. Also, the linker peptide can be removed without inactivating catalysis. In Leishmania donovani, separate OPRTase does not have detectable activity possibly due to lower thermal stability or lack of its linker peptide.