Current Topics in Medicinal Chemistry

Allen B. Reitz
Fox Chase Chemical Diversity Center, Inc.
Doylestown, PA
USA

Back

The Central Role of Angiotensin I-Converting Enzyme in Vertebrate Pathophysiology

Author(s): David W. Moskowitz and Frank E. Johnson

Affiliation: GenoMed, Inc., 909 S. Taylor,Ave., St. Louis, MO 63110, USA

Abstract:

Genomic epidemiologic data, increasingly supported by clinical outcomes results, strongly suggest that overactivity of angiotensin I-converting enzyme (ACE) may underlie most age-related diseases. Angiotensin II, the main product of ACE, is a pleiotropic hormone, capable of serving as a neurotransmitter, growth factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. So it is perhaps not surprising that the ACE D / D genotype is associated with several major psychiatric diseases, most cancers except prostate cancer (where the D / D genotype is actually protective), most cardiovascular diseases, most autoimmune diseases, and even infectious diseases like tuberculosis and HIV. In a preliminary study, angiotensin II blockade appeared to hasten recovery from West Nile virus encephalitis; it may be equally useful in SARS. The ACE gene underwent duplication at the origin of Chordata, just before the “Cambrian Explosion” in the number of species. The ancestral, unduplicated form of ACE is still expressed during the terminal differentiation of human spermatocytes, suggesting a critical role in reproduction. The crystal structure of testicular ACE (tACE) was recently published. Computer modeling suggests that tACE may be activated by both mechanical forces and reducing agents. The duplicated form of ACE (somatic ACE, sACE) is expressed in areas of high fluid flow. sACE may auto-dimerize via a novel protein motif, the “disulfide zipper.” The sACE dimer is predicted to have higher catalytic efficiency and redox resistance than tACE.

Keywords: aging, redox, cancer, disulfide zipper, autodimer

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

VOLUME: 4
ISSUE: 13
Page: [1431 - 1452]
Pages: 22
DOI: 10.2174/1568026043387818
Price: $58