The Enzymic Synthesis of Pyrimidines

Reichard, Peter

doi:10.1002/9780470122662.ch6

Cited by 8 publications

(4 citation statements)

References 122 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Orotidine monophosphate decarboxylase (ODCase, EC 4.1.1.23) is among the most proficient enzymes known . In human, ODCase is a part of the bifunctional enzyme UMP synthase . In bacteria and parasites, ODCase is a monofunctional enzyme. , It is involved in the catalytic decarboxylation of orotidine monophosphate (OMP, 1 ) to uridine monophosphate (UMP, 2 ), which in its triphosphate form is a constituent of RNA as well as a precursor for the synthesis of other pyrimidine nucleotides (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

Design of Inhibitors of Orotidine Monophosphate Decarboxylase Using Bioisosteric Replacement and Determination of Inhibition Kinetics

et al. 2006

View full text Add to dashboard Cite

Inhibitors of orotidine monophosphate decarboxylase (ODCase) have applications in RNA viral, parasitic, and other infectious diseases. ODCase catalyzes the decarboxylation of orotidine monophosphate (OMP), producing uridine monophosphate (UMP). Novel inhibitors 6-amino-UMP and 6-cyano-UMP were designed on the basis of the substructure volumes in the substrate OMP and in an inhibitor of ODCase, barbituric acid monophosphate, BMP. A new enzyme assay method using isothermal titration calorimetry (ITC) was developed to investigate the inhibition kinetics of ODCase. The reaction rates were measured by monitoring the heat generated during the decarboxylation reaction of orotidine monophosphate. Kinetic parameters (k(cat) = 21 s(-1) and KM = 5 microM) and the molar enthalpy (DeltaH(app) = 5 kcal/mol) were determined for the decarboxylation of the substrate by ODCase. Competitive inhibition of the enzyme was observed and the inhibition constants (Ki) were determined to be 12.4 microM and 29 microM for 6-aza-UMP and 6-cyano-UMP, respectively. 6-Amino-UMP was found to be among the potent inhibitors of ODCase, having an inhibition constant of 840 nM. We reveal here the first inhibitors of ODCase designed by the principles of bioisosterism and a novel method of using isothermal calorimetry for enzyme inhibition studies.

show abstract

Section: Introductionmentioning

confidence: 99%

Design of Inhibitors of Orotidine Monophosphate Decarboxylase Using Bioisosteric Replacement and Determination of Inhibition Kinetics

et al. 2006

View full text Add to dashboard Cite

show abstract

“…In humans, ODCase is part of the bifunctional enzyme UMP synthase, and, in lower level organisms, it is a monofunctional enzyme. 3,4,5 …”

Section: Introductionmentioning

confidence: 99%

“…Orotidine 5′-monophosphate decarboxylase (ODCase or OMPDCase, 4.1.1.23) catalyzes the transformation of orotidine 5′- O -monophosphate (OMP, 1 ) to uridine 5′- O -monophosphate (UMP, 2 ) during the de novo synthesis of pyrimidine nucleotides (Figure ). , UMP is a precursor for the synthesis of other pyrimidine nucleoside triphosphates, which in turn are precursors for the synthesis of ribonucleic and deoxyribonucleic acids. In humans, ODCase is part of the bifunctional enzyme UMP synthase, and in lower level organisms, it is a monofunctional enzyme. − …”

Section: Introductionmentioning

confidence: 99%

Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5′-Monophosphate Decarboxylase

et al. 2011

View full text Add to dashboard Cite

Fluorinated nucleosides and nucleotides are of considerable interest to medicinal chemists due to their antiviral, anticancer, and other biological activities. However, their direct interactions at target binding sites are not well understood. A new class of 2′-deoxy-2′-fluoro-C6-substituted uridine and UMP derivatives were synthesized and evaluated as inhibitors of orotidine-5′-monophosphate decarboxylase (ODCase). These compounds were synthesized from the key intermediate, fully-protected 2′-deoxy-2′-fluorouridine. Among the synthesized compounds, 2′-deoxy-2′-fluoro-6-iodo-UMP covalently inhibited human ODCase with a second-order rate constant of 0.62 ± 0.02 M−1sec−1. Interestingly, the 6-cyano-2′-fluoro derivative covalently interacted with ODCase defying the conventional thinking, where its ribosyl derivative undergoes transformation into BMP by ODCase. This confirms that the 2′-fluoro moiety influences the chemistry at the C6 position of the nucleotides, thus interactions in the active site of ODCase. Molecular interactions of the 2′-fluorinated nucleotides are compared to those with the 3′-fluorinated nucleotides bound to the corresponding target enzyme, and the carbohydrate moieties were shown to bind in different conformations.

show abstract

“…7 While in pathogenic organisms, such as bacteria, fungi and parasites, ODCase is a monofunctional enzyme, although in Plasmodia it forms a heterotetramer with orotate phosphoribosyltransferase. 8,9,10 In all species, ODCase seems to be active as a dimer and the catalytic site is comprised of active residues from the second monomer.…”

Section: Introductionmentioning

confidence: 99%

Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase

Meza‐Avina

Wei

Liu

et al. 2010

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

In recent years, orotidine-5′-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleotides including the mononucleotide derivatives of pyrazofurin, barbiturate ribonucleoside, and 5-cyanouridine, as well as, in a computational approach, 1,4-dihydropyridine-based non-nucleoside inhibitors such as nifedipine and nimodipine. All these ligands bind in the active site of ODCase exhibiting distinct interactions paving the way to design novel inhibitors against this interesting enzyme. We propose an empirical model for the ligand structure for rational modifications in new drug design and potentially new lead structures.

show abstract

The Enzymic Synthesis of Pyrimidines

Cited by 8 publications

References 122 publications

Design of Inhibitors of Orotidine Monophosphate Decarboxylase Using Bioisosteric Replacement and Determination of Inhibition Kinetics

Design of Inhibitors of Orotidine Monophosphate Decarboxylase Using Bioisosteric Replacement and Determination of Inhibition Kinetics

Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5′-Monophosphate Decarboxylase

Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase

Contact Info

Product

Resources

About