Electronic structure and reactivity of heme bound insulin

Abstract

Insulin resistance as well as insulin deficiency are said to be principal to the development of type 2 diabetes mellitus (T2Dm). Heme has also been suggested to play an important role in the disease etiology since many of the heme deficiency symptoms constitute the common pathological features of T2Dm. Besides, iron overload, higher heme iron intake and transfusion requiring diseases are associated with a higher risk of T2Dm development. In this study the interaction between these two key components [Formula: see text]. heme and insulin has been studied spectroscopically under different conditions which include the effect of excess peptide as well as increasing pH. The resultant heme-insulin complexes in their reduced state are found to produce very little partially reduced oxygen species (PROS) on getting oxidized by molecular oxygen. The interaction between insulin and previously reported T2Dm relevant heme-amylin complex were also examined using absorption and resonance Raman spectroscopy. The corresponding data suggest that insulin sequesters heme from heme-amylin to form the much less cytotoxic heme-insulin.

Second Sphere Interactions in Amyloidogenic Diseases

“…Spectroscopic techniques have indicated that heme can bind insulin in equimolar ratio in in vitro physiological conditions. This binding is offered via the His residue (5th/10th position in the B chain) of insulin peptide. , A molecular docking experiment supports that His5 of insulin is the binding ligand with heme-Fe. In addition to this, there are contributions of second sphere amino acids like Tyr26 and Phe1 residues, which promote hydrophobic/electrostatic interaction and Val2, which forms H-bond to the heme center, thus assisting in heme–insulin active site formation .…”

“…Studies have suggested that heme can parallelly bind to insulin as well, which is the complementary peptide of hIAPP and plays essential role in T2Dm etiology. These heme–insulin complexes also contribute to the oxidative and nitrative stress related complications in disease pathogenesis. , …”

“…Moreover, at higher pH, both high spin and low spin complexes show that the weakly bound water molecule, present at the axial sixth position of active site, is converted to a hydroxide bound high spin species. The heme­(II)-insulin complexes produce only 8–12% ROS . Significantly, they can amplify the peroxidase activity of free heme which under oxidative and nitrative stressed conditions is known to affect the disease pathogenesis via promoting Tyr radical and associated insulin cross-linking, leading to permanent loss of natural insulin functionality and by enhancing the tyrosine nitration of insulin in the β-cells that may result in inactivation of proteins related to diabetes as well. , …”

“…These heme−insulin complexes also contribute to the oxidative and nitrative stress related complications in disease pathogenesis. 396,397 3.3.2.1. Active Site Environment of Heme-hIAPP and Impact of Second Sphere.…”

The Role of Heme and Copper in Alzheimer’s Disease and Type 2 Diabetes Mellitus

“…The associated p K a of 1:1 heme-insulin complex is found to be 8.5 ± 0.2 which corresponds well to the H2O ↔ OH- equilibrium alike, the heme proteins such as myoglobin having a water derived ligand distal to the heme center ( Figure 3 A). 74 …”