Interaction of hemorphins with ACE homologs

Abstract

Hemorphins, short bioactive peptides produced by enzymatic cleavage of β-hemoglobin, exhibit antihypertensive properties by inhibiting angiotensin-1 converting enzyme (ACE1). ACE1 is a key player in the renin–angiotensin system (RAS) and regulates blood pressure. ACE1 and its homolog, ACE2, which exhibit opposing activities in the RAS, share considerable similarity in their catalytic domains. The primary objective of this study was to identify and contrast the molecular mechanisms underlying the interaction of hemorphins of camels and that of other mammals with the two ACE homologs. In silico docking and molecular dynamics simulations were performed for ACE1 and ACE2, along with in vitro confirmatory assays for ACE1. The C-domain of ACE1, primarily involved in regulating blood pressure, was used along with the N-terminal peptidase domain of ACE2. The findings revealed conserved hemorphin interactions with equivalent regions of the two ACE homologs and differential residue-level interactions reflecting the substrate preferences of ACE1 and ACE2 considering their opposing functions. Therefore, conserved residue-level associations and implications of poorly conserved regions between the two ACE receptors may potentially guide the discovery of selective domain-specific inhibitors. The findings of this study can provide a basis for the treatment of related disorders in the future.

In Silico Screening of Bioactive Peptides in Stout Beer and Analysis of ACE Inhibitory Activity

“…It was observed that DLGGFFGFQR formed eight hydrogen bonds with amino acids Cys352, Gln369, Val380, Pro407, His410, Gly408, and Gly414 in ACE, and the residues may enhance the ability of ACE to immobilize peptides and enhance stability, which may lead to increased inhibition. Based on relevant experimental reports and the findings related to the catalytic mechanism of ACE, it could be inferred that the results were similar to those for hemorphins [46]. Furthermore, DLGGFFGFQR formed 27 hydrophobic interactions with ACE and the action sites exhibited were different.…”

Computational Modeling of the Interactions between DPP IV and Hemorphins

“…These molecules work as opioid receptor ligands by exhibiting affinity for μ-, δ- and k-receptors and show antinociceptive activity [ 21 ]. Effects of hemorphins on the renin-angiotensin system (RAS), the kinin-kallikrein system (KKS) and insulin-regulating aminopeptidase (IRAP) are also documented [ 22 , 23 ]. Apart from this, these peptides are also reported to modulate the activity of calcineurin and Ca 2+ /calmodulin-dependent systems [ 24 ].…”

Synthesis, characterization, and biological study of new synthetic opioid hemorphin‐4 peptides containing sterically restricted nonnatural amino acids

“…[11] Some hemorphins are thought to be involved in blood pressure control by blocking both angiotensinconverting enzymes. [12] The affinity of the endogenous hemorphins for insulin-regulatory aminopeptidase suggests that they may act as analogs of angiotensin IV in regulating more complex brain functions such as memory. [13] Looking through the literature, certain nonnatural amino acids have been recognized as interesting profiles due to their effects on biologically active compounds with potential application in drug design and medicinal chemistry, once they have been inserted in peptide chains as novel unnatural building blocks.…”

“…[ 11 ] Some hemorphins are thought to be involved in blood pressure control by blocking both angiotensin‐converting enzymes. [ 12 ] The affinity of the endogenous hemorphins for insulin‐regulatory aminopeptidase suggests that they may act as analogs of angiotensin IV in regulating more complex brain functions such as memory. [ 13 ]…”