Current View from Alzheimer Disease to Type 2 Diabetes Mellitus

Rasool, Mahmood; Malik, Arif; Qazi, Aamer; Sheikh, Ishfaq Ahmed; Manan, Abdul; Shaheen, Sumaira; Qazi, Mahmood Husain; Chaudhary, Adeel; Abuzenadah, Adel M.; Asif, Muhammad; Al-Qahtani, Mohammed H.; Iqbal, Zafar; Shaik, Munvar Miya; Gan, Siew Hua; Kamal, Mohammad Amjad

doi:10.2174/18715273113126660167

Cited by 16 publications

(9 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Insulin degrading enzyme (IDE) is an evolutionary conserved zinc metalloprotease that is included in the M16 family and is characterized by an 'inverted' motif of the active site sequence H 108 XXEH [1,2]. Extensive in vivo and genetic studies have highlighted the relevant role of IDE in insulin and b-amyloid (Ab) catabolism, outlining the involvement of IDE in Alzheimer's disease (AD) and diabetes mellitus type 2 (DM2) pathogenesis [3][4][5][6][7][8][9][10]. In addition, IDE cleaves several short bioactive peptides (such as insulin-like growth factor, amylin, glucagon, transforming growth factor-a and atrial natriuretic peptides), which show a common propensity to form b-sheet-rich amyloid fibrils, even though they differ significantly both in sequence and length [1,[11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Multiple allosteric sites are involved in the modulation of insulin‐degrading‐enzyme activity by somatostatin

et al. 2016

View full text Add to dashboard Cite

Somatostatin is a cyclic peptide, released in the gastrointestinal system and the central nervous system, where it is involved in the regulation of cognitive and sensory functions, motor activity and sleep. It is a substrate of insulin-degrading enzyme (IDE), as well as a modulator of its activity and expression. In the present study, we have investigated the modulatory role of somatostatin on IDE activity at 37 °C and pH 7.3 for various substrates [i.e. insulin, β-amyloid (Aβ) and bradykinin], aiming to quantitatively characterize the correlation between the specific features of the substrates and the regulatory mechanism. Functional data indicate that somatostatin, in addition to the catalytic site of IDE (being a substrate), is also able to bind to two additional exosites, which play different roles according to the size of the substrate and its binding mode to the IDE catalytic cleft. In particular, one exosite, which displays high affinity for somatostatin, regulates only the interaction of IDE with larger substrates (such as insulin and Aβ ) in a differing fashion according to their various modes of binding to the enzyme. A second exosite, which is involved in the regulation of enzymatic processing by IDE of all substrates investigated (including a 10-25 amino acid long amyloid-like peptide, bradykinin and somatostatin itself, which had been studied previously), probably acts through the alteration of an 'open-closed' equilibrium.

show abstract

Section: Introductionmentioning

confidence: 99%

Multiple allosteric sites are involved in the modulation of insulin‐degrading‐enzyme activity by somatostatin

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Moreover, drug receptors are also encoded by polymorphic genes [ 39 ] and mutations in receptors, such as the receptor tyrosine kinases, have been linked to various cancers and neurodegenerative diseases [ 41 - 44 ]. For example, over-expression of ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) in breast cancer is treated with trastuzumab [ 43 ], the BCR/ABL fusion protein is highly sensitive to imatinib in the case of leukemia [ 41 ] and activating mutations of epidermal growth factor receptor (EGFR) seem to correlate with the responsiveness to gefitinib [ 42 ].…”

Section: Pharmacogenomics and Personalized Medicinesmentioning

confidence: 99%

The role of epigenetics in personalized medicine: challenges and opportunities

et al. 2015

Self Cite

View full text Add to dashboard Cite

Epigenetic alterations are considered to be very influential in both the normal and disease states of an organism. These alterations include methylation, acetylation, phosphorylation, and ubiquitylation of DNA and histone proteins (nucleosomes) as well as chromatin remodeling. Many diseases, such as cancers and neurodegenerative disorders, are often associated with epigenetic alterations. DNA methylation is one important modification that leads to disease. Standard therapies are given to patients; however, few patients respond to these drugs, because of various molecular alterations in their cells, which may be partially due to genetic heterogeneity and epigenetic alterations. To realize the promise of personalized medicine, both genetic and epigenetic diagnostic testing will be required. This review will discuss the advances that have been made as well as the challenges for the future.

show abstract

“…4c), the two N-terminal b-sheets of Ab and hIAPP were associated together and stacked in an antiparallel orientation to form a NN interface. The a CN h _14 interface formed hydrophobic interactions between V 24 , F 20 , and V 18 of Ab and A 13 , F 15 , and V 17 of hIAPP, salt bridges between E 22 of Ab and R 11 of hIAPP, and p-p stacking between F 20 of Ab and F 15 of hIAPP. With diverse stabilizing forces, electrostatic interactions were dominant occupying 90% of total interfacial energy.…”

Section: Interfacial Interactions Of Ab-hiapp Assembliesmentioning

confidence: 99%

Polymorphic cross-seeding amyloid assemblies of amyloid-β and human islet amyloid polypeptide

Zhang

Chen

et al. 2015

Phys. Chem. Chem. Phys.

View full text Add to dashboard Cite

Epidemiological studies have shown that the development of Alzheimer's disease (AD) is associated with type 2 diabetes (T2D), but it still remains unclear how AD and T2D are connected. Heterologous cross-seeding between the causative peptides of Aβ and hIAPP may represent a molecular link between AD and T2D. Here, we computationally modeled and simulated a series of cross-seeding double-layer assemblies formed by Aβ and hIAPP peptides using all-atom and coarse-gained molecular dynamics (MD) simulations. The cross-seeding Aβ-hIAPP assemblies showed a wide range of polymorphic structures via a combination of four β-sheet-to-β-sheet interfaces and two packing orientations, focusing on a comparison of different matches of β-sheet layers. Two cross-seeding Aβ-hIAPP assemblies with different interfacial β-sheet packings exhibited high structural stability and favorable interfacial interactions in both oligomeric and fibrillar states. Both Aβ-hIAPP assemblies displayed interfacial dehydration to different extents, which in turn promoted Aβ-hIAPP association depending on interfacial polarity and geometry. Furthermore, computational mutagenesis studies revealed that disruption of interfacial salt bridges largely disfavor the β-sheet-to-β-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. This work provides atomic-level information on the cross-seeding interactions between Aβ and hIAPP, which may be involved in the interplay between these two disorders.

show abstract

Current View from Alzheimer Disease to Type 2 Diabetes Mellitus

Cited by 16 publications

References 74 publications

Multiple allosteric sites are involved in the modulation of insulin‐degrading‐enzyme activity by somatostatin

Multiple allosteric sites are involved in the modulation of insulin‐degrading‐enzyme activity by somatostatin

The role of epigenetics in personalized medicine: challenges and opportunities

Polymorphic cross-seeding amyloid assemblies of amyloid-β and human islet amyloid polypeptide

Contact Info

Product

Resources

About