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Crystal structure of orotate phosphoribosyltransferase.
Biochemistry. 1994 Feb 15; 33(6):1287-94.B

Abstract

Phosphoribosyltransferases (PRTases) are enzymes involved in the synthesis of purine, pyrimidine, and pyridine nucleotides. They utilize alpha-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and a nitrogenous base to form a beta-N-riboside monophosphate and pyrophosphate (PPi), and their functional significance in nucleotide homeostasis is evidenced by the devastating effects of inherited diseases associated with the decreased activity and/or stability of these enzymes. The 2.6-A structure of the Salmonella typhimurium orotate phosphoribosyltransferase (OPRTase) complexed with its product orotidine monophosphate (OMP) provides the first detailed image of a member of this group of enzymes. The OPRTase three-dimensional structure was solved using multiple isomorphous replacement methods and reveals two major features: a core five-stranded alpha/beta twisted sheet and an N-terminal region that partially covers the C-terminal portion of the core. PRTases show a very high degree of base specificity. In OPRTase, this is determined by steric constraints and the position of hydrogen bond donors/acceptors of a solvent-inaccessible crevice where the orotate ring of bound OMP resides. Crystalline OPRTase is a dimer, with catalytically important residues from each subunit available to the neighboring subunit, suggesting that oligomerization is necessary for its activity. On the basis of the presence of a common PRPP binding motif among PRTases and the similar chemistry these enzymes perform, we propose that the alpha/beta core found in OPRTase will represent a common feature for PRTases. This generality is demonstrated by construction of a model of the human hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) from secondary structure predictions for HGPRTase and the three-dimensional structure of OPRTase.

Authors+Show Affiliations

Scapin G
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461.
Grubmeyer C
No affiliation info available
Sacchettini JC
No affiliation info available

MeSH

Amino Acid SequenceBinding SitesCrystallizationCrystallography, X-RayElectrochemistryHydrogen BondingHypoxanthine PhosphoribosyltransferaseMacromolecular SubstancesModels, MolecularMolecular Sequence DataMolecular StructureNucleotidesOrotate PhosphoribosyltransferaseProtein Structure, Secondary

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8312245

Citation

Scapin, G, et al. "Crystal Structure of Orotate Phosphoribosyltransferase." Biochemistry, vol. 33, no. 6, 1994, pp. 1287-94.
Scapin G, Grubmeyer C, Sacchettini JC. Crystal structure of orotate phosphoribosyltransferase. Biochemistry. 1994;33(6):1287-94.
Scapin, G., Grubmeyer, C., & Sacchettini, J. C. (1994). Crystal structure of orotate phosphoribosyltransferase. Biochemistry, 33(6), 1287-94.
Scapin G, Grubmeyer C, Sacchettini JC. Crystal Structure of Orotate Phosphoribosyltransferase. Biochemistry. 1994 Feb 15;33(6):1287-94. PubMed PMID: 8312245.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Crystal structure of orotate phosphoribosyltransferase. AU - Scapin,G, AU - Grubmeyer,C, AU - Sacchettini,J C, PY - 1994/2/15/pubmed PY - 1994/2/15/medline PY - 1994/2/15/entrez SP - 1287 EP - 94 JF - Biochemistry JO - Biochemistry VL - 33 IS - 6 N2 - Phosphoribosyltransferases (PRTases) are enzymes involved in the synthesis of purine, pyrimidine, and pyridine nucleotides. They utilize alpha-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and a nitrogenous base to form a beta-N-riboside monophosphate and pyrophosphate (PPi), and their functional significance in nucleotide homeostasis is evidenced by the devastating effects of inherited diseases associated with the decreased activity and/or stability of these enzymes. The 2.6-A structure of the Salmonella typhimurium orotate phosphoribosyltransferase (OPRTase) complexed with its product orotidine monophosphate (OMP) provides the first detailed image of a member of this group of enzymes. The OPRTase three-dimensional structure was solved using multiple isomorphous replacement methods and reveals two major features: a core five-stranded alpha/beta twisted sheet and an N-terminal region that partially covers the C-terminal portion of the core. PRTases show a very high degree of base specificity. In OPRTase, this is determined by steric constraints and the position of hydrogen bond donors/acceptors of a solvent-inaccessible crevice where the orotate ring of bound OMP resides. Crystalline OPRTase is a dimer, with catalytically important residues from each subunit available to the neighboring subunit, suggesting that oligomerization is necessary for its activity. On the basis of the presence of a common PRPP binding motif among PRTases and the similar chemistry these enzymes perform, we propose that the alpha/beta core found in OPRTase will represent a common feature for PRTases. This generality is demonstrated by construction of a model of the human hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) from secondary structure predictions for HGPRTase and the three-dimensional structure of OPRTase. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/8312245/Crystal_structure_of_orotate_phosphoribosyltransferase_ L2 - https://www.yeastgenome.org/reference/8312245 DB - PRIME DP - Unbound Medicine ER -