Cited by 35Protein Kinase Regulation and GTPase SignalingPancreatic function and diabetesSphingolipid Metabolism and Signaling

Targeting Small GTPases and Their Prenylation in Diabetes Mellitus

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Gendaszewska-Darmach, Edyta, Garstka, Malgorzata A., Błażewska, Katarzyna M.·2021·Journal of Medicinal Chemistry

Abstract

A fundamental role of pancreatic β-cells to maintain proper blood glucose level is controlled by the Ras superfamily of small GTPases that undergo post-translational modifications, including prenylation. This covalent attachment with either a farnesyl or a geranylgeranyl group controls their localization, activity, and protein-protein interactions. Small GTPases are critical in maintaining glucose homeostasis acting in the pancreas and metabolically active tissues such as skeletal muscles, liver, or adipocytes. Hyperglycemia-induced upregulation of small GTPases suggests that inhibition of these pathways deserves to be considered as a potential therapeutic approach in treating T2D. This Perspective presents how inhibition of various points in the mevalonate pathway might affect protein prenylation and functioning of diabetes-affected tissues and contribute to chronic inflammation involved in diabetes mellitus (T2D) development. We also demonstrate the currently available molecular tools to decipher the mechanisms linking the mevalonate pathway's enzymes and GTPases with diabetes.

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Crossref · 10.1021/acs.jmedchem.1c00410

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  • Small GTPases need post-translational modification to target them to cellular membranes and be active.

    “All these small GTPase need post-translational modification to target them to cellular membranes and be active [16,17].”

    From Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome (2022) · cites this paper as [17]

    The Overview of Superfamily of Small GTPases and Enzymes within the Mevalonate Pathway (page unavailable) says small GTPases usually carry a post-translationally attached prenyl tail and explains that masking this tail prevents Rho and Rab from associating with target membranes. It does not establish that all small GTPases require modification to become active; it describes activation as the exchange of GDP for GTP. (LLM, conf=0.87)

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  1. Chen F.; Zhang N.; Ma D.; Ma X.; Huang T.; Wang Q. Effect of the Rho Kinase Inhibitor Y-27632 and Fasudil on Inflammation and Fibrosis in Human Mesangial Cells (HMCs) under High Glucose via the Rho/ROCK Signaling Pathway. Int. J. Clin. Exp. Med. 2017, 10, 13224– 13234.

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Authors
Gendaszewska-Darmach, E., Garstka, M. A., & Błażewska, K. M.
Affiliations
  • Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego Street 4/10, 90-924 Łódź, Poland
  • Second Affiliated Hospital of Xi'an Jiaotong University (CN)
  • Lodz University of Technology (PL)
Corresponding author
  • Garstka, Malgorzata A.
  • Błażewska, Katarzyna M.
Venue
Journal of Medicinal Chemistry
Published
2021-07-08
Volume
64
Issue
14
Pages
9677-9710
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W3181493345
Cited by
35
References
301
Citations by year
2026: 6 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 12 · 2021: 2
FWCI
0.66
Type
journal article
Language
en
Open access
Locations
  • Journal of Medicinal Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Narodowe Centrum Nauki (2014/14/E/ST5/00491, 2018/31/B/NZ9/02433)
  • Second Affiliated Hospital, Xiâ??an Jiaotong University (82668330, 82668428)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords
small GTPases, Ras superfamily, protein prenylation, farnesyltransferase, geranylgeranyltransferase, mevalonate pathway, type 2 diabetes, pancreatic beta cells, glucose homeostasis, hyperglycemia, chronic inflammation, GTPase inhibitors, therapeutic target
MeSH terms
Animals, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Hypoglycemic Agents, Structure-Activity Relationship, Molecular Structure, Monomeric GTP-Binding Proteins

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