Thermodynamic analysis of transition-state features in picomolar inhibitors of human 5′-methylthioadenosine phosphorylase

Rong Guan, Peter C. Tyler, Gary B. Evans, Vern L. Schramm

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Human 5′-methylthioadenosine phosphorylase (MTAP) is solely responsible for 5′-methylthioadenosine (MTA) metabolism to permit S-adenosylmethionine salvage. Transition-state (TS) analogues of MTAP are in development as anticancer candidates. TS analogues of MTAP incorporate a cationic nitrogen and a protonated 9-deazaadenine leaving group, which are mimics of the ribocation transition state. MT-ImmA and MT-DADMe-ImmA are two examples of these TS analogues. Thermodynamic analysis of MTA, inhibitor, and phosphate binding reveals the cationic nitrogen to provide-2.6 and-3.6 kcal/mol binding free energy for MT-ImmA and MT-DADMe-ImmA, respectively. The protonated deazaadenine provides an additional-1.3 (MT-ImmA) to-1.7 kcal/mol (MT-DADMe-ImmA). MT-DADMe-ImmA is a better match in TS geometry than MT-ImmA and is thermodynamically favored. Binding of TS analogues to the MTAP/phosphate complex is fully entropic, in contrast to TS analogue binding to the related human purine nucleoside phosphorylase/phosphate complex, which is fully enthalpic (Guan, R., Ho, M. C., Brenowitz, M., Tyler, P. C., Evans, G. B., Almo, S. C., and Schramm, V. L. (2011) Biochemistry 50, 10408-10417). The binding thermodynamics of phosphate or TS analogues alone to MTAP are fully dominated by enthalpy. Phosphate anchored in the catalytic site forms an ion pair with the cationic TS analogue to cause stabilization of the enzyme structure in the ternary complex. The ternary-induced conformational changes convert the individual enthalpic binding energies to entropy, resulting in a presumed shift of the protein architecture toward the transition state. Formation of the ternary TS analogue complex with MTAP induces a remarkable increase in thermal stability (ΔTm 28 C). The enthalpic, entropic, and protein-stability features of TS analogue binding to human MTAP are resolved in these studies.

Original languageEnglish (US)
Pages (from-to)8313-8322
Number of pages10
JournalBiochemistry
Volume52
Issue number46
DOIs
StatePublished - Nov 19 2013

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Thermodynamics
Phosphates
Nitrogen
Purine-Nucleoside Phosphorylase
Salvaging
S-Adenosylmethionine
Biochemistry
Protein Stability
Entropy
5'-methylthioadenosine phosphorylase
Binding energy
Metabolism
Free energy
Enthalpy
Catalytic Domain
Proteins
Thermodynamic stability
Stabilization
Hot Temperature
Ions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Thermodynamic analysis of transition-state features in picomolar inhibitors of human 5′-methylthioadenosine phosphorylase. / Guan, Rong; Tyler, Peter C.; Evans, Gary B.; Schramm, Vern L.

In: Biochemistry, Vol. 52, No. 46, 19.11.2013, p. 8313-8322.

Research output: Contribution to journalArticle

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abstract = "Human 5′-methylthioadenosine phosphorylase (MTAP) is solely responsible for 5′-methylthioadenosine (MTA) metabolism to permit S-adenosylmethionine salvage. Transition-state (TS) analogues of MTAP are in development as anticancer candidates. TS analogues of MTAP incorporate a cationic nitrogen and a protonated 9-deazaadenine leaving group, which are mimics of the ribocation transition state. MT-ImmA and MT-DADMe-ImmA are two examples of these TS analogues. Thermodynamic analysis of MTA, inhibitor, and phosphate binding reveals the cationic nitrogen to provide-2.6 and-3.6 kcal/mol binding free energy for MT-ImmA and MT-DADMe-ImmA, respectively. The protonated deazaadenine provides an additional-1.3 (MT-ImmA) to-1.7 kcal/mol (MT-DADMe-ImmA). MT-DADMe-ImmA is a better match in TS geometry than MT-ImmA and is thermodynamically favored. Binding of TS analogues to the MTAP/phosphate complex is fully entropic, in contrast to TS analogue binding to the related human purine nucleoside phosphorylase/phosphate complex, which is fully enthalpic (Guan, R., Ho, M. C., Brenowitz, M., Tyler, P. C., Evans, G. B., Almo, S. C., and Schramm, V. L. (2011) Biochemistry 50, 10408-10417). The binding thermodynamics of phosphate or TS analogues alone to MTAP are fully dominated by enthalpy. Phosphate anchored in the catalytic site forms an ion pair with the cationic TS analogue to cause stabilization of the enzyme structure in the ternary complex. The ternary-induced conformational changes convert the individual enthalpic binding energies to entropy, resulting in a presumed shift of the protein architecture toward the transition state. Formation of the ternary TS analogue complex with MTAP induces a remarkable increase in thermal stability (ΔTm 28 C). The enthalpic, entropic, and protein-stability features of TS analogue binding to human MTAP are resolved in these studies.",
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