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

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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
DOI 10.1021/acs.jmedchem.1c00410PMC PMC8389838
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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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Figures

Figure 1 Small GTPase cycle: (A) Interaction with GEF mediates the exchange of GDP for GTP, allows activation, interaction with effectors, and initiation of the signal cascade. Interaction with GAP increases GTP hydrolysis, leading to G protein deactivation. Interaction with GDI keeps small GTPase in an off-state and prevents membrane localization. (B) The conserved architecture of the G domain present in small GTPases (for sequence alignment of Rab, Rho and Ras GTPases implicated in diabetes, see Supplementary Figure S1). (C) Crystal structures of Rab7a: left, inactivated (GDP-bound, PDB; 1VG1); middle, activated (GTP-bound, PDB: 1VG8); right, with its effector RILP (PDB: 1YHN, only part of RILP interacting with Rab7a is shown). (D) Crystal structures of Rac1: left, inactivated (GDP-bound, PDB: 6AGP), middle, activated (GNP-bound, PDB: 3TH5); right, with its effector PRex1 (PDB: 4YON, only domains of PREx1 interacting with Rac1(a1, a5, and a6) are shown). (E) Crystal structures of HRas: left, inactivated (GDP-bound, PDB: 4Q21); middle, activated (GTP-bound; PDB: 1QRA); right, with RasGAP (PDB: 1WQ1). The P loop is represented in orange, switch I in green, switch II in magenta, coordinated magnesium ion in black, GDP in dark blue, and GTP or GTP analogues in cyan. GNP: phosphoaminophosphonic acid-guanylate ester nonhydrolyzable GTP analogue. The corresponding Supplementary Table 1 contains the list of PDB codes for mammalian small GTPases implicated in diabetes, in GDP and GTP-bound form, with effector/GEF/GAP, when available.
Figure 1 Small GTPase cycle: (A) Interaction with GEF mediates the exchange of GDP for GTP, allows activation, interaction with effectors, and initiation of the signal cascade. Interaction with GAP increases GTP hydrolysis, leading to G protein deactivation. Interaction with GDI keeps small GTPase in an off-state and prevents membrane localization. (B) The conserved architecture of the G domain present in small GTPases (for sequence alignment of Rab, Rho and Ras GTPases implicated in diabetes, see Supplementary Figure S1). (C) Crystal structures of Rab7a: left, inactivated (GDP-bound, PDB; 1VG1); middle, activated (GTP-bound, PDB: 1VG8); right, with its effector RILP (PDB: 1YHN, only part of RILP interacting with Rab7a is shown). (D) Crystal structures of Rac1: left, inactivated (GDP-bound, PDB: 6AGP), middle, activated (GNP-bound, PDB: 3TH5); right, with its effector PRex1 (PDB: 4YON, only domains of PREx1 interacting with Rac1(a1, a5, and a6) are shown). (E) Crystal structures of HRas: left, inactivated (GDP-bound, PDB: 4Q21); middle, activated (GTP-bound; PDB: 1QRA); right, with RasGAP (PDB: 1WQ1). The P loop is represented in orange, switch I in green, switch II in magenta, coordinated magnesium ion in black, GDP in dark blue, and GTP or GTP analogues in cyan. GNP: phosphoaminophosphonic acid-guanylate ester nonhydrolyzable GTP analogue. The corresponding Supplementary Table 1 contains the list of PDB codes for mammalian small GTPases implicated in diabetes, in GDP and GTP-bound form, with effector/GEF/GAP, when available.CC BY · PubMed Central
Figure 2 Schematic representation of mevalonate pathway. HMG-CoA reductase catalyzes the formation of mevalonate from HMG-CoA. FPPS mediates further conversion to GPP and FPP. FTase catalyzes attachment of FPP to Ras, Rho, and Rheb proteins (in the process called farnesylation). GGPPS catalyzes the conversion of FPP to GGPP that can be post-translationally added to RhoA, RAc1, Cd42, Ral, and Rap by GGTase-I, Rab proteins by GGTase-II, and Ykt6 and FBXL2 by GGTase-III.
Figure 2 Schematic representation of mevalonate pathway. HMG-CoA reductase catalyzes the formation of mevalonate from HMG-CoA. FPPS mediates further conversion to GPP and FPP. FTase catalyzes attachment of FPP to Ras, Rho, and Rheb proteins (in the process called farnesylation). GGPPS catalyzes the conversion of FPP to GGPP that can be post-translationally added to RhoA, RAc1, Cd42, Ral, and Rap by GGTase-I, Rab proteins by GGTase-II, and Ykt6 and FBXL2 by GGTase-III.CC BY · PubMed Central
Figure 3 Structural overview of enzymes within the mevalonate pathway and prenyltransferases. (A) HMG-CoA reductase (PDB: 1DQ9) is a homotetramer. Each subunit comprises an N domain (in green), large L domains (in magenta), and an S domain (in light blue). (B) FPPS (PDB: 5JA0) PO4 in red. (C) GGPPS (PDB: 2Q80) is a hexameter composed of three dimers: chain A–B (in pink), chain C–D (in green), and chain E–F (in blue). Mg2+ is represented in black, and GRG in dark blue. (D) Comparison of structures of prenyltransferases: FTase (PDB: 1FPP), GGTase-I (PDB: 1N4P), GGTase-II (PDB: 3DST), and GGTase-III (PDB: 6J6X). The α and β subunits are color-coded, and the shared domains have the same color. Zn2+ is presented in black. The corresponding Supplementary Table S2 contains the list of PDB codes for mammalian enzymes within the mevalonate pathway and prenyltransferases implicated in diabetes, in GDP and GTP-bound form, with substrate/product/inhibitor, when available.
Figure 3 Structural overview of enzymes within the mevalonate pathway and prenyltransferases. (A) HMG-CoA reductase (PDB: 1DQ9) is a homotetramer. Each subunit comprises an N domain (in green), large L domains (in magenta), and an S domain (in light blue). (B) FPPS (PDB: 5JA0) PO4 in red. (C) GGPPS (PDB: 2Q80) is a hexameter composed of three dimers: chain A–B (in pink), chain C–D (in green), and chain E–F (in blue). Mg2+ is represented in black, and GRG in dark blue. (D) Comparison of structures of prenyltransferases: FTase (PDB: 1FPP), GGTase-I (PDB: 1N4P), GGTase-II (PDB: 3DST), and GGTase-III (PDB: 6J6X). The α and β subunits are color-coded, and the shared domains have the same color. Zn2+ is presented in black. The corresponding Supplementary Table S2 contains the list of PDB codes for mammalian enzymes within the mevalonate pathway and prenyltransferases implicated in diabetes, in GDP and GTP-bound form, with substrate/product/inhibitor, when available.CC BY · PubMed Central
Figure 4 Schematic representation of insulin synthesis and trafficking and exocytosis of insulin containing granules (created in BioRender.com). Proinsulin processing occurs in the lumen of ER and insulin is stored as a hexamer in complex with Zn2+. Glucose enters the cells and via mitochondrial ATP synthesis raises the ATP-to-ADP ratio, causing the ATP-sensitive K+ (KATP) channels to close. Following cellular depolarization, VGGC is activated, causing extracellular Ca2+ influx and insulin granule fusion with the plasma membrane. Specific sets of Rab GTPases regulate insulin secretory granule transport, endocytosis, and the three main stages of insulin granule exocytosis (docking, priming, and fusion). For the sake of simplicity, we have not included all the specific Rabs involved that have been described in Table 1.
Figure 4 Schematic representation of insulin synthesis and trafficking and exocytosis of insulin containing granules (created in BioRender.com). Proinsulin processing occurs in the lumen of ER and insulin is stored as a hexamer in complex with Zn2+. Glucose enters the cells and via mitochondrial ATP synthesis raises the ATP-to-ADP ratio, causing the ATP-sensitive K+ (KATP) channels to close. Following cellular depolarization, VGGC is activated, causing extracellular Ca2+ influx and insulin granule fusion with the plasma membrane. Specific sets of Rab GTPases regulate insulin secretory granule transport, endocytosis, and the three main stages of insulin granule exocytosis (docking, priming, and fusion). For the sake of simplicity, we have not included all the specific Rabs involved that have been described in Table 1.CC BY · PubMed Central
Figure 5 Scheme of the insulin-regulated transport of GLUT4 vesicles translocation and exocytosis (created in BioRender.com). Insulin binds the insulin receptor that induces the translocation of GLUT4 storage vesicles by activating the PI3K signaling cascade. PI3K catalyzes the formation of phosphatidylinositol (3,4,5) trisphosphate leading to the action of PDK1, which in turn stimulates Akt. Activated Akt phosphorylates and inactivates GAPs (e.g., TBC1D1, TBC1D4, RGC1/2). GAPs inhibition shifts small GTPases from the GDP- to a more active GTP-loaded state. Rac1 facilitates GLUT4 plasma membrane association via actin filament remodeling. GTP-loaded Rabs and other Ras superfamily members permit GLUT4 storage vesicle translocation to the cell surface for fusion. In addition to the main PI3K pathway, the Rho family GTPases (e.g., RhoA, Cdc42, TC10) mediate insulin signaling in regulating GLUT4 translocation. For the sake of clarity, we have not included all the specific Rabs involved that have been described in Table 2.
Figure 5 Scheme of the insulin-regulated transport of GLUT4 vesicles translocation and exocytosis (created in BioRender.com). Insulin binds the insulin receptor that induces the translocation of GLUT4 storage vesicles by activating the PI3K signaling cascade. PI3K catalyzes the formation of phosphatidylinositol (3,4,5) trisphosphate leading to the action of PDK1, which in turn stimulates Akt. Activated Akt phosphorylates and inactivates GAPs (e.g., TBC1D1, TBC1D4, RGC1/2). GAPs inhibition shifts small GTPases from the GDP- to a more active GTP-loaded state. Rac1 facilitates GLUT4 plasma membrane association via actin filament remodeling. GTP-loaded Rabs and other Ras superfamily members permit GLUT4 storage vesicle translocation to the cell surface for fusion. In addition to the main PI3K pathway, the Rho family GTPases (e.g., RhoA, Cdc42, TC10) mediate insulin signaling in regulating GLUT4 translocation. For the sake of clarity, we have not included all the specific Rabs involved that have been described in Table 2.CC BY · PubMed Central
Figure 6 Dual effect of statins on inflammation in diabetes. Statins exert anti-inflammatory effects via (1) reducing chemoattractant levels in the circulation; (2) reducing proinflammatory signaling pathways in blood leukocytes; (3) reducing VLA-4 and FLA-1 integrin levels on blood monocytes and lymphocytes; (4) reducing VCAM-1 and ICAM-1 levels on endothelial cells; (5) reducing MMP1 production by macrophages. These effects result in the inhibition of leukocyte recruitment from the blood into the tissue. Statins exert proinflammatory effects via (6) activation of the NLRP3 inflammasome in insulin-sensitive tissue that leads to enhanced production of IL-1β. IL-1β autostimulation amplifies inflammation and attracts immune cells
Figure 6 Dual effect of statins on inflammation in diabetes. Statins exert anti-inflammatory effects via (1) reducing chemoattractant levels in the circulation; (2) reducing proinflammatory signaling pathways in blood leukocytes; (3) reducing VLA-4 and FLA-1 integrin levels on blood monocytes and lymphocytes; (4) reducing VCAM-1 and ICAM-1 levels on endothelial cells; (5) reducing MMP1 production by macrophages. These effects result in the inhibition of leukocyte recruitment from the blood into the tissue. Statins exert proinflammatory effects via (6) activation of the NLRP3 inflammasome in insulin-sensitive tissue that leads to enhanced production of IL-1β. IL-1β autostimulation amplifies inflammation and attracts immune cellsCC BY · PubMed Central
Figure 7 Structures of the selected GGPPS inhibitors not used in diabetes studies.
Figure 7 Structures of the selected GGPPS inhibitors not used in diabetes studies.CC BY · PubMed Central
Figure 8 Structures of the selected GGTase-II (RGGT) inhibitors not used in diabetes studies. LED: lowest effective dose toward inhibition of Rab11 prenylation.
Figure 8 Structures of the selected GGTase-II (RGGT) inhibitors not used in diabetes studies. LED: lowest effective dose toward inhibition of Rab11 prenylation.CC BY · PubMed Central

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Metadata

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.
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2021-07-08
Volume
64
Issue
14
Pages
9677-9710
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.1c00410
PMC
PMC8389838
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
Licence
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 › Endocrinology, Diabetes and Metabolism › 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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