Is "Somatic" Angiotensin I-Converting Enzyme a Mechanosensor?

Abstract

"Somatic" angiotensin I-converting enzyme (ACE) appears to be one of the evolutionary advances that made a closed circulation possible, and may have contributed to the Cambrian "explosion" of species approximately 540 million years ago. It also appears to be at the origin of a large number of common human diseases. A model is proposed in which the duplicated form of ACE ("somatic" ACE) functions as a mechanotransducer, defending downstream vessels and tissues from an increase in pressure. In the model, ACE senses shear stress (blood velocity) in regions of turbulent blood flow. An increase in shear stress strips an autoinhibitor tripeptide, FQP, from the N-terminal active site, thereby activating it. The C-terminal domain is constitutively activated by chloride. This model explains the clinical superiority of hydrophobic ACE inhibitors relative to hydrophilic ones.

Defatted Jatropha curcas flour and protein isolate as materials for protein hydrolysates with biological activity

“…A model, proposed to explain the clinical superiority of hydrophobic ACE-I inhibitory drugs versus hydrophilic ones, states that all ACE inhibitors bind to the C-terminal catalytic site, but only hydrophobic ones bind to the occluded N-terminal catalytic site and are therefore better at blocking angiotensin II production. This would also explain why hydrophobic ACE-I inhibitors have specific local benefits such as organ damage prevention, in addition to reducing blood pressure (Moskowitz, 2003). ACE inhibitory activity in the analyzed hydrolysates depended significantly on protein source (defatted J. curcas flour or protein isolate) and enzymatic system.…”

ACE-I inhibitory properties of hydrolysates from germinated and ungerminated Phaseolus lunatus proteins

“…The above-mentioned show the importance of hydrophobic residues in the biological potential of the peptide fractions from P. lunatus. Moskowitz (2002) proposed a model explaining the clinical superiority of hydrophobic ACE inhibitory drugs relative to hydrophilic ones: all ACE inhibitors bind to the C-terminal catalytic site, but only hydrophobic ones bind to the occluded N-terminal catalytic site and are therefore better at blocking angiotensin II production. This would also explain why hydrophobic ACE inhibitors have specific local benefits such as organ damage prevention, in addition to reducing blood pressure.…”

Genetically encoded force sensors for measuring mechanical forces in proteins

“…[3][4][5] All proteins are mechanosensitive since they are elastic-these properties are at the heart of molecular dynamic computations. [6][7][8] Numerous studies have also indicated that mechanical forces can regulate gene expression. [9][10][11][12] There are feedback loops incorporating cancer malignancy and metastasis, 17,18 blood vessel angiogenesis, [19][20][21][22] bone growth and osteoporosis and lung, heart and skeleton muscle metabolism.…”