Sodium 5,6-dihydrouracil-6-sulfonate monohydrate

Barnes, Charles L.; Hawkinson, S. W.

doi:10.1107/s0567740880008953

Cited by 4 publications

(5 citation statements)

References 7 publications

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“…In each of these molecules, the pyrimidine ring is somewhat puckered because of the presence of a saturated C 5 -C 6 bond, and the C 6 substituents may be axially or equatorially oriented with respect to the dihydropyrimidine ring. Earlier analysis (20) of dihydroorotic acid showed that the carboxylate group tends to prefer an axial position, and the crystal structure of 5,6-dihydrouracil-6-sulfonate (21) shows the sulfonate group axially oriented at C 6 . It seems reasonable to suppose that the same may be true of the sulfonyl group of UMP-6-SO 3 and of the carboxylate of 5,6dihydro-OMP.…”

Section: Discussionmentioning

confidence: 99%

“…These authors suggest that the hydroxyl group of Ser-127 forms a strong H-bond to N 3 of 6-aza-UMP and that a backbone -NH group forms a H-bond to the 4-carbonyl 4 In OMP, the carbon atom of the C6 carboxyl group lies in the same plane as the atoms of the pyrimidine ring, but the steric demands of the anomeric H1′ atom force the two oxygens to be oriented nearly perpendicular to the ring, so that the -COOgroup is in position to be impacted by electrostatic stress. In contrast, the carboxylate of 5,6dihydro-OMP or the sulfonate group of 5,6-dihydro-UMP-6-sulfonate can occupy an axial position, potentially relieving the stress (20,21), but in 5,6-dihydro-OMP-6-sulfonate with the carboxylate group and the sulfonate group on C6, one would expect one of these groups to be equatorial. The crystal structure of 5,6-dihydrouracil-6-sulfonate (21) shows that the axial sulfonate group displaces C6 and N1 out of the plane of the other four atoms of the pyrimidine ring by 0.763 and 0.206 Å, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the carboxylate of 5,6dihydro-OMP or the sulfonate group of 5,6-dihydro-UMP-6-sulfonate can occupy an axial position, potentially relieving the stress (20,21), but in 5,6-dihydro-OMP-6-sulfonate with the carboxylate group and the sulfonate group on C6, one would expect one of these groups to be equatorial. The crystal structure of 5,6-dihydrouracil-6-sulfonate (21) shows that the axial sulfonate group displaces C6 and N1 out of the plane of the other four atoms of the pyrimidine ring by 0.763 and 0.206 Å, respectively. In contrast, the equatorial proton on C6 is oriented downward near the plane of the ring.…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of these considerations and modeling of several complexes of ODCase from M. thermoautotrophicum containing various uracil derivatives (Supporting Information), we present hypothetical structures of UMP-SO 3 and OMP-SO 3 bound within the active site of the enzyme (Figure 12). These structures are derived from the well-characterized complex of ODCase with BMP and structural data for 5,6dihydrouracil-6-sulfonate (21). The puckered dihydropyrimidine ring of each adduct is oriented in such a way as to be superimposed on the pyrimidine ring of BMP as closely as possible.…”

Section: Discussionmentioning

confidence: 99%

“…The summing of the OMP from the OMP-sulfonate adduct and the OMP added as substrate solution produced no significant differences in calculated K I values (Figure 9).5,6-Dihydro-6-Sulfonates of UMP and OMP Inhibit ODCase 4 In OMP, the carbon atom of the C 6 carboxyl group lies in the same plane as the atoms of the pyrimidine ring, but the steric demands of the anomeric H 1 atoms force the two oxygens be oriented nearly perpendicular to the ring, so that the -COO − group is in position to be impacted by electrostatic stress. In contrast, the carboxylate of 5,6-dihydro-OMP or the sulfonate group of 5,6-dihydro-UMP-6sulfonate can occupy an axial position, potentially relieving the stress (20,21). But, in 5,6-dihydro-OMP-6-sulfonate with the carboxylate group and the sulfonate group on C 6 , one would expect one of these groups to be equatorial.…”

mentioning

confidence: 99%

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Indiscriminate Binding by Orotidine 5‘-Phosphate Decarboxylase of Uridine 5‘-Phosphate Derivatives with Bulky Anionic C₆ Substituents

Lewis

Wolfenden

2007

Biochemistry

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Orotidine 5'-phosphate (OMP) decarboxylase appears to act upon its substrate without the intervention of metals or other cofactors and without the formation of covalent bonds between the enzyme and the substrate. Crystallographic information indicates that substrate binding forces the substrate's scissile carboxylate group into the neighborhood of several charged groups at the active site. It has been proposed that binding might result in electrostatic stress at the substrate's C6 carboxylate group in such a way as to promote decarboxylation by destabilizing the enzyme-substrate complex in its ground state. If that were the case, one would expect uridine 5'-phosphate (UMP) derivatives with bulky anionic substituents at C6 to be bound weakly compared with UMP, which is unsubstituted at C6. Here, we describe the formation of anionic 5,6-dihydro-6-sulfonyl derivatives by spontaneous addition of sulfite to UMP and to OMP. These sulfite addition reactions, which are slowly reversible and are not catalyzed by the enzyme, result in the appearance of one (or, in the case of OMP, two) bulky anionic substituents at the 6-carbon atom of UMP. These inhibitors are bound with affinities that surpass the binding affinity of UMP. We are led to infer that the active site of OMP decarboxylase is remarkably accommodating in the neighborhood of C6. These are not the properties that one would expect of an active site with a rigid structure that imposes sufficient electrostatic stress on the substrate to produce a major advancement along the reaction coordinate.

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Section: Discussionmentioning

confidence: 99%