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Protein prenylation: enzymes, therapeutics, and biotechnology applications.

Palsuledesai CC, Distefano MD - ACS Chem. Biol. (2014)

Bottom Line: It is essential for the proper cellular activity of numerous proteins, including Ras family GTPases and heterotrimeric G-proteins.Inhibition of prenylation has been extensively investigated to suppress the activity of oncogenic Ras proteins to achieve antitumor activity.Finally, we discuss recent progress in utilizing protein prenylation for site-specific protein labeling for various biotechnology applications.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.

ABSTRACT
Protein prenylation is a ubiquitous covalent post-translational modification found in all eukaryotic cells, comprising attachment of either a farnesyl or a geranylgeranyl isoprenoid. It is essential for the proper cellular activity of numerous proteins, including Ras family GTPases and heterotrimeric G-proteins. Inhibition of prenylation has been extensively investigated to suppress the activity of oncogenic Ras proteins to achieve antitumor activity. Here, we review the biochemistry of the prenyltransferase enzymes and numerous isoprenoid analogs synthesized to investigate various aspects of prenylation and prenyltransferases. We also give an account of the current status of prenyltransferase inhibitors as potential therapeutics against several diseases including cancers, progeria, aging, parasitic diseases, and bacterial and viral infections. Finally, we discuss recent progress in utilizing protein prenylation for site-specific protein labeling for various biotechnology applications.

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Structures of isoprenoidanalogs used to study structure, mechanism, and isoprenoid substratespecificity of FTase and GGTase-I.
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fig6: Structures of isoprenoidanalogs used to study structure, mechanism, and isoprenoid substratespecificity of FTase and GGTase-I.

Mentions: A large number of isoprenoid analogs containing various functionalitieshave been synthesized to study a variety of aspects of the prenylationreaction and prenyltransferases. Before the crystal structure of FTasewas solved, photoaffinity probes such as compounds 6–9 (Figure 6) were used extensivelyto probe the structural features of yeast and mammalian variants ofFTase and GGTase-I.29,54−61 These analogs revealed the role of the β-subunit of FTaseand GGTase-I in the recognition and binding of isoprenoid substrates,as well as indicated differences between active site architectureof mammalian and yeast FTases. Later, similar experiments were alsocarried out with GGTase-II, which led to identification of proteinswith which Rab5 interacts via the isoprenoid group.62 Interestingly, it was noted that while 8 wasaccepted as a substrate by FTase, 9, containing one moreisoprenoid unit, was a potent inhibitor of yeast FTase.63,64 Recently, a new photoactive isoprenoid probe containing a diazirinegroup (10) was reported whose size more closely approximatesthat of FPP. Peptides incorporating that photoactive isoprenoid wereused in cross-linking studies of Icmt.65 Phosphonate 11 and related analogs66 have been particularly useful for crystallographic studiesthat have revealed that the isoprenoid binds in an extended conformationand that several active site residues undergo rearrangement upon isoprenoidbinding compared with the unliganded enzyme.67


Protein prenylation: enzymes, therapeutics, and biotechnology applications.

Palsuledesai CC, Distefano MD - ACS Chem. Biol. (2014)

Structures of isoprenoidanalogs used to study structure, mechanism, and isoprenoid substratespecificity of FTase and GGTase-I.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4301080&req=5

fig6: Structures of isoprenoidanalogs used to study structure, mechanism, and isoprenoid substratespecificity of FTase and GGTase-I.
Mentions: A large number of isoprenoid analogs containing various functionalitieshave been synthesized to study a variety of aspects of the prenylationreaction and prenyltransferases. Before the crystal structure of FTasewas solved, photoaffinity probes such as compounds 6–9 (Figure 6) were used extensivelyto probe the structural features of yeast and mammalian variants ofFTase and GGTase-I.29,54−61 These analogs revealed the role of the β-subunit of FTaseand GGTase-I in the recognition and binding of isoprenoid substrates,as well as indicated differences between active site architectureof mammalian and yeast FTases. Later, similar experiments were alsocarried out with GGTase-II, which led to identification of proteinswith which Rab5 interacts via the isoprenoid group.62 Interestingly, it was noted that while 8 wasaccepted as a substrate by FTase, 9, containing one moreisoprenoid unit, was a potent inhibitor of yeast FTase.63,64 Recently, a new photoactive isoprenoid probe containing a diazirinegroup (10) was reported whose size more closely approximatesthat of FPP. Peptides incorporating that photoactive isoprenoid wereused in cross-linking studies of Icmt.65 Phosphonate 11 and related analogs66 have been particularly useful for crystallographic studiesthat have revealed that the isoprenoid binds in an extended conformationand that several active site residues undergo rearrangement upon isoprenoidbinding compared with the unliganded enzyme.67

Bottom Line: It is essential for the proper cellular activity of numerous proteins, including Ras family GTPases and heterotrimeric G-proteins.Inhibition of prenylation has been extensively investigated to suppress the activity of oncogenic Ras proteins to achieve antitumor activity.Finally, we discuss recent progress in utilizing protein prenylation for site-specific protein labeling for various biotechnology applications.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.

ABSTRACT
Protein prenylation is a ubiquitous covalent post-translational modification found in all eukaryotic cells, comprising attachment of either a farnesyl or a geranylgeranyl isoprenoid. It is essential for the proper cellular activity of numerous proteins, including Ras family GTPases and heterotrimeric G-proteins. Inhibition of prenylation has been extensively investigated to suppress the activity of oncogenic Ras proteins to achieve antitumor activity. Here, we review the biochemistry of the prenyltransferase enzymes and numerous isoprenoid analogs synthesized to investigate various aspects of prenylation and prenyltransferases. We also give an account of the current status of prenyltransferase inhibitors as potential therapeutics against several diseases including cancers, progeria, aging, parasitic diseases, and bacterial and viral infections. Finally, we discuss recent progress in utilizing protein prenylation for site-specific protein labeling for various biotechnology applications.

Show MeSH
Related in: MedlinePlus