UTP—glucose-1-phosphate uridylyltransferase

UTP—glucose-1-phosphate uridylyltransferase also known as glucose-1-phosphate uridylyltransferase (or UDP–glucose pyrophosphorylase) is an enzyme involved in carbohydrate metabolism. It synthesizes UDP-glucose from glucose-1-phosphate and UTP; i.e.,Crystal structure of UTP—glucose-1-phosphate uridylyltransferase from Burkholderia xenovoransHuman UTP—glucose-1-phosphate uridylyltransferase isoform 1 subunit with UDP-glucose bound UTP—glucose-1-phosphate uridylyltransferase also known as glucose-1-phosphate uridylyltransferase (or UDP–glucose pyrophosphorylase) is an enzyme involved in carbohydrate metabolism. It synthesizes UDP-glucose from glucose-1-phosphate and UTP; i.e., UTP—glucose-1-phosphate uridylyltransferase is an enzyme found in all three domains (bacteria, eukarya, and archaea) as it is a key player in glycogenesis and cell wall synthesis. Its role in sugar metabolism has been studied extensively in plants in order to understand plant growth and increase agricultural production. Recently, human UTP—glucose-1-phosphate uridylyltransferase has been studied and crystallized, revealing a different type of regulation than other organisms previously studied. Its significance is derived from the many uses of UDP-glucose including galactose metabolism, glycogen synthesis, glycoprotein synthesis, and glycolipid synthesis. The structure of UTP—glucose-1-phosphate uridylyltransferase is significantly different between prokaryotes and eukaryotes, but within eukaryotes, the primary, secondary, and tertiary structures of the enzyme are quite conserved. In many species, UTP—glucose-1-phosphate uridylyltransferase is found as a homopolymer consisting of identical subunits in a symmetrical quaternary structure. The number of subunits varies across species: for instance, in Escherichia coli, the enzyme is found as a tetramer, whereas in Burkholderia xenovorans, the enzyme is dimeric. In humans and in yeast, the enzyme is active as an octamer consisting of two tetramers stacked onto one another with conserved hydrophobic residues at the interfaces between the subunits. In contrast, the enzyme in plants has conserved charged residues forming the interface between subunits. In humans, each enzyme subunit contains several residues (L113, N251, and N328) that are highly conserved in eukaryotes. A Rossman fold motif participates in binding of the UTP nucleotide and a sugar-binding domain (residues T286–G293) coordinates with the glucose ring. A missense mutation (G115D) in the region of the enzyme containing the active site (which is conserved in eukaryotes) causes a dramatic decrease in enzymatic activity in vitro. Human genes encoding proteins with UTP—glucose-1-phosphate uridylyltransferase activity include two isoforms with molecular weights of 56.9 and 55.7 kDa, respectively. UTP—glucose-1-phosphate uridylyltransferase is ubiquitous in nature due to its important role in the generation of UDP-glucose, a central compound in carbohydrate metabolism. In plant leaves, UTP—glucose-1-phosphate uridylyltransferase is a key part of the sucrose biosynthesis pathway, supplying Uridine diphosphate glucose to Sucrose-phosphate synthase which converts UDP-glucose and D-fructose 6-phosphate into sucrose-6-phosphate. It may also be partially responsible for the breakdown of sucrose in other tissues using UDP-glucose. In higher animals, the enzyme is highly active in tissues involved in glycogenesis, including the liver and the muscles. An exception is the brain, which has high levels of glycogen but low specific activity of UTP—glucose-1-phosphate uridylyltransferase. In animal cells, UTP—glucose-1-phosphate uridylyltransferase is found predominantly in the cytoplasm. UTP—glucose-1-phosphate uridylyltransferase is also required for galactose metabolism in animals and microorganisms. In galactose metabolism, the enzyme galactose 1-phosphate uridylyltransferase transfers a phosphate from UDP-glucose to galactose 1-phosphate to produce UDP-galactose, which is then converted to UDP-glucose. Bacteria with defective UTP—glucose-1-phosphate uridylyltransferase are unable to incorporate galactose into their cell walls. In this enzyme’s primary reaction, the phosphate group on glucose-1-phosphate replaces the phosphoanhydride bond on UTP. This reaction is readily reversible and the Gibbs Free Energy is close to zero. However, under typical cellular conditions, inorganic pyrophosphatase quickly hydrolyzes the pyrophosphate product and drives the reaction forward by Le Chatelier's Principle.