Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo

Durham, Timothy B.; Toth, John E.; Klimkowski, V. J.; Cao, Julia Xiao-Chun; Siesky, Angela M.; Alexander-Chacko, Jesline; Wu, Ginger; Dixon, Jeffrey T.; McGee, J; Wang, Yong; Guo, Sherry; cavitt, Rachel; Schindler, John; Thibodeaux, Stefan Jon; Calvert, Nathan A; Coghlan, Michael J.; Sindelar, Dana K.; Christe, Michael E.; Kiselyov, Vladislav V.; Michael, M. Dodson; Sloop, Kyle W.

doi:10.1074/jbc.m115.638205

Cited by 43 publications

(76 citation statements)

References 43 publications

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“…In turn, using a structurebased approach, Durham et al designed a series of novel dual exosite-binding IDE inhibitors which do not interact with the catalytic zinc of the protease (50). However, as published in the literature, only two of abovementioned IDE inhibitors were tested in vivo and demonstrated stability, pharmacokinetic properties and physiological effects, thus confirming their potential for the development of antidiabetic drugs (47,50). The results of these studies are described in detail below.…”

Section: Development Of Chemical Modulators Of Ide Activitymentioning

confidence: 74%

“…Further, prolonged IDE inhibition may lead to amyloid deposition and cytotoxicity in pancreatic beta-cells (46) (Figure 1). Paradoxically, Durham et al found no action of another (dual-exosite) IDE inhibitor NTE-1 on insulin and glucagon degradation in vivo, although it resulted in elevated plasma amylin levels and improved glucose excursion in oral glucose tolerance test (50). Authors hypothesized that these contradictory findings may be explained by differences in biochemical mechanisms of action or biodistribution of 6bK and NTE-1, but further experimentation is needed to clarify this.…”

Section: Compoundmentioning

confidence: 91%

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Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

et al. 2016

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Insulin-degrading enzyme (IDE) is a major enzyme responsible for insulin degradation. In addition to insulin, IDE degrades many targets including glucagon, atrial natriuretic peptide, and betaamyloid peptide, regulates proteasomal degradation and other cell functions. IDE represents a pathophysiological link between type 2 diabetes (T2DM) and late onset Alzheimer's disease (AD). Potent and selective modulators of IDE activity are potential drugs for therapies of both diseases. Acute treatment with a novel IDE inhibitor was recently tested in a mouse study as a therapeutic approach for the treatment of T2DM. In contrast, effective IDE activators can be used for the AD treatment. However, because of the pleiotropic IDE action, the sustained treatment with systemic IDE modulators should be carefully tested in animal studies. Development of substrate-selective IDE modulators could overcome possible adverse effects of IDE modulators associated with multiplicity of IDE targets. KEY MESSAGESInsulin-degrading enzyme (IDE) represents a pathophysiological link between type 2 diabetes (T2DM) and Alzheimer's disease (AD). Selective modulators of IDE activity are potential drugs for both T2DM and AD treatment. Development of substrate-selective IDE modulators could overcome possible adverse effects of IDE modulators associated with multiplicity of IDE targets. ARTICLE HISTORY

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Section: Development Of Chemical Modulators Of Ide Activitymentioning

confidence: 74%

Section: Compoundmentioning

confidence: 91%

Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

et al. 2016

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“…However, Durham et al (10) found that an IDE inhibitor did not increase plasma insulin levels or improve insulin sensitization, and concluded that IDE plays only a limited role in insulin clearance. Moreover, Steneberg et al (9) reported that IDE knockout mice did not exhibit elevated fasting insulin levels, in contrast to other findings.…”

Section: Ide Localization To Endosomes Involves the Polyanion-bindingmentioning

confidence: 99%

“…Evidence supporting a role for IDE in degrading insulin and Aβ in vivo includes associations of IDE gene variants with type 2 diabetes (1, 2) and Alzheimer's disease (3,4), decreased clearance of the two peptides in IDE-deficient mice (5,6), and antidiabetic activity produced by IDE inhibitors (7,8), although some reports have questioned its role in insulin degradation (9,10). In addition, IDE has been reported to have noncatalytic functions, such as acting as a receptor for varicella-zoster virus (11) and serving as a heat shock protein in stressed cells (12).…”

mentioning

confidence: 99%

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

Song

Jang

Guo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily V max . The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed. IDE binds PtdInsPs from solution, immobilized on membranes, or presented in liposomes. Interaction with PtdInsPs, likely PtdIns(3)P, plays a role in localizing IDE to endosomes, where the enzyme reportedly encounters physiological substrates. Thus, InsPs and PtdInsPs can serve as endogenous modulators of IDE activity, as well as regulators of its intracellular spatial distribution.insulin-degrading enzyme | inositols | phosphatidylinositols | activation | subcellular localization I nsulin-degrading enzyme (IDE), also known as insulysin (EC 3.4.24.56), hydrolyzes a broad range of bioactive peptides in vitro, including angiotensin, glucagon, β-endorphin, amylin, and amyloid β peptides (Aβ), with the two most established in vivo substrates being insulin and Aβ. Evidence supporting a role for IDE in degrading insulin and Aβ in vivo includes associations of IDE gene variants with type 2 diabetes (1, 2) and Alzheimer's disease (3, 4), decreased clearance of the two peptides in IDE-deficient mice (5, 6), and antidiabetic activity produced by IDE inhibitors (7, 8), although some reports have questioned its role in insulin degradation (9, 10). In addition, IDE has been reported to have noncatalytic functions, such as acting as a receptor for varicella-zoster virus (11) and serving as a heat shock protein in stressed cells (12). IDE also modulates the activity of the proteasome (13), reportedly in conjunction with the retinoblastoma tumor-suppressor protein (14).We previously established that polyanions, such as free ATP and triphosphate, increase IDE activity by up to 100-fold toward a synthetic peptide substrate (15) and that ATP binds to a strongly electropositive inner surface of IDE that forms one-half of the substrate-binding chamber (16,17). Significantly, mutations in IDE that reduce its activation by polyanions also decrease its ability to rescue production of a mature yeast mating factor, indicating that activation by polyanions plays an important physiological role in cells (16). Physiological polyanionic activators of IDE have not yet been identified, however.Inositol phosphates (InsPs) are important intracellular second messengers generated by activation of many cell surface receptors (18,19). Phosphatidylinositol phosphates (PtdInsPs; phosphoinositides) participate in signaling and help define the identity of subcellular compartment...

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“…Recently, a novel class of IDE inhibitors was discovered, but these compounds do not interact with the catalytic zinc of the protease. Instead, the inhibitors bind to the dual exosite of IDE (57). The co-crystallization of the N-terminal tag acting as a pseudo-substrate with PqqF provides a novel idea for future designs of IDE inhibitors.…”

Section: D-glucose-mediated Inhibition Of Prodigiosin Production-mentioning

confidence: 99%

Crystal Structure and Function of PqqF Protein in the Pyrroloquinoline Quinone Biosynthetic Pathway

Wei

Ran

et al. 2016

Journal of Biological Chemistry

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Pyrroloquinoline quinone (PQQ) has received considerable attention due to its numerous important physiological functions. PqqA is a precursor peptide of PQQ with two conserved residues: glutamate and tyrosine. After linkage of the C␥ of glutamate and C⑀ of tyrosine by PqqE, these two residues are hypothesized to be cleaved from PqqA by PqqF. The linked glutamate and tyrosine residues are then used to synthesize PQQ. Here, we demonstrated that the pqqF gene is essential for PQQ biosynthesis as deletion of it eliminated the inhibition of prodigiosin production by glucose. We further determined the crystal structure of PqqF, which has a closed clamshell-like shape. The PqqF consists of two halves composed of an N-and a C-terminal lobe. The PqqF-N and PqqF-C lobes form a chamber with the volume of the cavity of ϳ9400 Å 3 . The PqqF structure conforms to the general structure of inverzincins. Compared with the most thoroughly characterized inverzincin insulin-degrading enzyme, the size of PqqF chamber is markedly smaller, which may define the specificity for its substrate PqqA. Furthermore, the 14-amino acid-residue-long tag formed by the N-terminal tag from expression vector precisely protrudes into the counterpart active site; this N-terminal tag occupies the active site and stabilizes the closed, inactive conformation. His-48, His-52, Glu-129 and His-14 from the N-terminal tag coordinate with the zinc ion. Glu-51 acts as a base catalyst. The observed histidine residue-mediated inhibition may be applicable for the design of a peptide for the inhibition of M16 metalloproteases.Pyrroloquinoline quinone (PQQ), 4 an aromatic orthoquinone, has been recognized as the third class of redox cofactors in addition to the well known cofactors, nicotinamide (NAD(P) ϩ ) and flavin (FAD, FMN) (1). PQQ was first identified from methanol dehydrogenase in methylotrophic bacteria (2), and several bacterial dehydrogenases, such as glucose dehydrogenases, quinate dehydrogenase, and alcohol dehydrogenase, were later found to be quinoproteins (3-5). Recently, sugar oxidoreductase in the basidiomycete Coprinopsis cinerea (6), 2-keto-D-glucose dehydrogenase from Pseudomonas aureofaciens (7) and pyranose dehydrogenase from C. cinerea (8) were all characterized as novel PQQ-dependent enzymes. Free PQQ has been identified in a wide variety of foods (9) and milk (10). PQQ is an essential nutrient for proper growth and development in mice (11). The strong-antioxidant capacity of PQQ protects living cells and biomolecules from oxidative stress in vivo and in vitro (12, 13). Furthermore, PQQ exerts a protective effect against ultraviolet irradiation-induced human dermal fibroblast senescence in vitro (14) and suppresses the serum low density cholesterol level to prevent various diseases (15). In addition, PQQ may improve skin conditions and slow the progression of osteoarthritis (16).The chemical structure of PQQ was determined in 1980 (17). Since then gene clusters involved in the synthesis of PQQ from different bacteria that range from 4 genes ...

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Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo

Cited by 43 publications

References 43 publications

Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

Crystal Structure and Function of PqqF Protein in the Pyrroloquinoline Quinone Biosynthetic Pathway

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