Protein Prenylation, Part B

Preface

The Enzymology of CAAX Protein Prenylation

I. Abstract

II. Introduction

III. Protein FTase

IV. Protein GGTase-I

V. Conclusions

Acknowledgments

CAAX Processing and Yeast a-Factor Biogenesis

I. Abstract

II. Introduction

III. The a-Factor Mating Pheromone of S. cerevisiae as an Early Prototype for Dissecting the CAAX-Processing Pathway

IV. Biogenesis Pathway of a-Factor: Genetic and Biochemical Analysis of the a-Factor Machinery

V. Progeria—The Role of Prenylation and ZMPSTE24 in Progeroid Disorders

VI. A Prenylated, Secreted Molecule Involved in Drosophila Germ Cell Migration Requires a Pathway Strikingly Similar to That of a-Factor Biogenesis

Acknowledgments

Prenylation and Phosphorylation of Ras Superfamily Small GTPases

I. Abstract

II. Introduction

III. Small GTPase Prenylation

IV. C-Terminal Phosphorylation of Prenylated Ras Family Small GTPases

V. C-Terminal Phosphorylation of Prenylated Rho Family Small GTPases

VI. C-Terminal Phosphorylation of Prenylated Rab Family Small GTPases

VII. Conclusions

Acknowledgments

Biochemical and Biological Functions of Isoprenylcysteine Carboxyl Methyltransferase

I. Abstract

II. Introduction

III. Icmt: Structure and Biological Function

IV. ICMT Substrate Specificity

V. Effect of Methylation by Icmt on Substrate Function: In Vitro Studies

VI. ICMT Effect on Substrate Function: In Vivo Studies

VII. Conclusions

Chemical Probes of Protein Prenylation

I. Abstract

II. Introduction

III. Prenyl Analogs as FTase Inhibitors (FTIs)

IV. Prenyl Analogs as Mechanistic and Structural Probes

V. Substrate Specificity Studies

VI. Prenyl Proteomics Studies

VII. Future Directions

Geranylgeranyltransferase-1 Inhibitors

I. Abstract

II. Introduction

III. Biochemistry of Protein Prenylation

IV. Validation of GGT-1 as a Target in a Genetic Mouse Model

V. Design of CaaX Peptidomimetics as PTIs and Identification of PTIs from High-Throughput Screens (HTS)

VI. FTIs as Anticancer Drugs

VII. GGTI Effects in Cultured Cells and In Vivo

VIII. GGTIs in the Clinic

IX. The Use of PTIs in Other Diseases

X. Future Directions and Challenges

Acknowledgments

Small-Molecule Inhibitors of GGTase-I from the Heterocycle Library Derived from Phosphine Catalysis

I. Abstract

II. Introduction

III. Phosphine Catalysis-Based Chemical Compound Library and Identification of Initial GGTI Compounds P3-E5 and P5-H6

IV. Cell Active Compound P61-A6

V. Tumor Growth Inhibition by P61-A6

VI. Long Plasma Half Life of P61-A6 and Pharmacokinetic Parameters

VII. Identification of Dual Specificity Inhibitors of GGTase-I and RabGGTase

VIII. Identification of Specific Inhibitors of RabGGTase from the Library

IX. Conclusion and Future Prospects

Acknowledgment

Inhibition of Rab Prenylation

I. Abstract

II. Introduction

III. RabGGTase Inhibitors

IV. Summary and Outlook

Inhibitors of Postprenylation CAAX Processing Enzymes

I. Abstract

II. Introduction

III. Inhibitors of Rce1

IV. Inhibitors of Icmt

V. Conclusion

The Ras Converting Enzyme (Rce1p)

I. Abstract

II. Introduction

III. Identification of Rce1p and Its Orthologs

IV. The Basis for Rce1p as a Therapeutic Target for Disease

V. Rce1p and Ste24p Have Different Target Specificities

VI. The Recognition of Specific CaaX Motifs is Influenced by Protein Context

VII. Rce1p Influences the Localization of Some But Not All of Its Targets

VIII. Rce1p Inhibitors Can Be Assay Independent and Assay Dependent

IX. Structural Chemistry and Proposed Mechanism

X. Conclusions and Future Directions

Acknowledgments

Cysmethynil, a Specific Small-Molecule Inhibitor of Isoprenylcysteine Carboxylmethyl Transferase (Icmt)

I. Abstract

II. Prenylation Process

III. Rationale for Targeting Icmt

IV. Icmt and Its Functional Importance in Biology

V. Development of Icmt Inhibitors

VI. Cysmethynil, a Nonstructure Analog Small-Molecule Inhibitor of Icmt

VII. Inhibition of Icmt by Cysmethynil Induces Autophagy and Cell Death, Potential for Cancer Therapy

VIII. Cysmethynil Inhibition of Icmt Results in Reduction of Rho-Mediated Cell Migration, Suggesting a Potential Role in Cancer Metastasis

IX. Current and Future Work to Identify Better Icmt Inhibitors Through Medicinal Chemistry

The Isoprenoid Biosynthetic Pathway and Statins

I. Abstract

II. The Isoprenoid Biosynthetic Pathway

III. Statins

IV. Statins and the IBP

V. Future Directions

Inhibition of Farnesyl and Geranylgeranyl Diphosphate Synthases

I. Abstract

II. The Isoprenoid Biosynthetic Pathway

III. Nitrogenous Bisphosphonates

IV. GGDPS Inhibitors

V. Future Directions