Exploration of GGTase-I substrate requirements. Part 1: Synthesis and biochemical evaluation of novel aryl-modified geranylgeranyl diphosphate analogs

Kayla J Temple; Elia N Wright; Carol A Fierke; Richard A Gibbs

doi:10.1016/j.bmcl.2016.06.034

Exploration of GGTase-I substrate requirements. Part 1: Synthesis and biochemical evaluation of novel aryl-modified geranylgeranyl diphosphate analogs

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3499-502. doi: 10.1016/j.bmcl.2016.06.034. Epub 2016 Jun 16.

Authors

Kayla J Temple¹, Elia N Wright², Carol A Fierke³, Richard A Gibbs⁴

Affiliations

¹ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47909, USA. Electronic address: [email protected].
² Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47909, USA.

Abstract

Protein geranylgeranylation is a type of post-translational modification that aids in the localization of proteins to the plasma member where they elicit cellular signals. To better understand the isoprenoid requirements of GGTase-I, a series of aryl-modified geranylgeranyl diphosphate analogs were synthesized and screened against mammalian GGTase-I. Of our seven-member library of compounds, six analogs proved to be substrates of GGTase-I, with 6d having a krel=1.93 when compared to GGPP (krel=1.0).

Keywords: Aryl-modified GGPP analogs; GGTase-I; Geranylgeranylation; Post-translational modification; Protein prenylation.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Alkyl and Aryl Transferases / metabolism
Animals
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Polyisoprenyl Phosphates / chemical synthesis
Polyisoprenyl Phosphates / chemistry
Polyisoprenyl Phosphates / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Polyisoprenyl Phosphates
Alkyl and Aryl Transferases
geranylgeranyltransferase type-I
geranylgeranyl pyrophosphate

Abstract

Publication types

MeSH terms

Substances

Grants and funding