Male fertility is dependent on dipeptidase activity of testis ACE

Fuchs, Sébastien; Frenzel, Kristen; Hübert, Christine; Lyng, Robert; Muller, Laurent; Michaud, Annie; Xiao, Hong; Adams, Jonathan; Capecchi, Mario R.; Corvol, Pierre; Shur, Barry D.; Bernstein, Kenneth E.

doi:10.1038/nm1105-1140

Cited by 74 publications

(56 citation statements)

References 10 publications

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“…The testis ACE isoform in mammals is similar in function in that the lack of tACE or the inactivation of its catalytic activity results in male sterility. 10 In contrast to male germ cells, somatic tissues produce ACE with 2 catalytic domains. However, even today, there is little insight into the specific advantage that this conferred in vertebrate evolution.…”

Section: Discussionmentioning

confidence: 99%

“…14 Because of the sterility of the homozygote males, we generated ACE13/13 mice by breeding heterozygote parents. 10 This procedure also allows us to generate homozygote mutant ACE13/13 mice with wild-type control mice in the same litter.…”

Section: Generation Of C-terminal Domain-inactivated Micementioning

confidence: 99%

“…We now know that it is the dipeptidyl peptidase function of tACE that is essential for normal male fertility. 10 However, the precise peptide substrates important in this process are, at present, not known.…”

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confidence: 99%

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Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

et al. 2008

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Abstract-Angiotensin-converting enzyme (ACE) plays a central role in the production of the vasoconstrictor angiotensin II. ACE is a single polypeptide, but it contains 2 homologous and independent catalytic domains, each of which binds zinc. To understand the in vivo role of these 2 domains, we used gene targeting to create mice with point mutations in the ACE C-domain zinc-binding motif. Such mice, termed ACE13/13, produce a full-length ACE protein with tissue expression identical to wild-type mice. Analysis of ACE13/13 mice showed that they produce ACE having only N-domain catalytic activity, as determined by the hydrolysis of domain specific substrates and by chloride sensitivity. ACE13/13 mice have blood pressure and blood angiotensin II levels similar to wild-type mice. However, plasma renin concentration is increased 2.6-fold and blood angiotensin I levels are increased 7.5-fold. Bradykinin peptide levels are not different from wild-type levels. ACE13/13 mice have a reduced increase of blood pressure after intravenous infusion of angiotensin I. ACE13/13 mice have a normal renal structure, but they are not able to concentrate urine after dehydration as effectively as wild-type mice. This study shows that the C-domain of ACE is the predominant site of angiotensin I cleavage in vivo. Although mice lacking C-domain activity have normal physiology under laboratory conditions, they respond less well to the stress of dehydration. (Hypertension. 2008;51:267-274.)

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Section: Discussionmentioning

confidence: 99%

Section: Generation Of C-terminal Domain-inactivated Micementioning

confidence: 99%

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Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

et al. 2008

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“…Angiotensin II might affect fertility in the human male because of its ability to stimulate sperm motility, induce the acrosome reaction and increase oocyte penetration (Kohn et al, 1997;Kohn et al, 1998;Vinson et al, 1996;Vinson et al, 1995). By contrast, the pronounced male infertility of mice lacking germinal ACE is independent of the RAS and probably results from failure to cleave a peptide distinct from angiotensin I (Fuchs et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Male accessory glands of Drosophila melanogaster make a secreted angiotensin I-converting enzyme (ANCE), suggesting a role for the peptide-processing enzyme in seminal fluid

Rylett

Walker

Howell

et al. 2007

Journal of Experimental Biology

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SUMMARY Angiotensin I-converting enzyme (ACE) expressed on the surface of endothelial cells is responsible for the last step in the synthesis of circulating angiotensin II and the inactivation of bradykinin. Mammalian ACE is also expressed in the prostate with other components of the renin–angiotensin system, and in developing spermatids, where the peptidase activity is known to be critical for normal sperm function. The importance of an ACE gene to male fertility has also been demonstrated in Drosophila melanogaster, where Ance is expressed in spermatids, and hypomorphic alleles of Ance cause a defect in spermiogenesis. Here we show that ANCE, which shares many enzymatic properties with mammalian ACE, is also a product of the male accessory gland of D. melanogaster. It is expressed in the secondary cells and is associated with the electron dense granule within the large vesicles of these cells. ACE proteolytic activity is lost from the accessory glands during mating,consistent with transfer to the mated female in the seminal fluid. The accessory gland ACE-like activity might have an evolutionarily conserved function processing biologically active peptides with a role in male fertility.

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“…Ace KO spermatozoa were defi cient in their ability to migrate into the oviduct and bind ZP in vitro, leading to the aberrant distribution of ADAM3 ( 84 ). Using sperm-adhesion molecule 1 (SPAM1/PH20) and PRSS21 (PRSS21/TESP5) as substrates, ACE also has GPIase activity in spermatozoa ( 7 ); however, the GPIase activity was mild and was not confi rmed by other groups ( 85,86 ).…”

Section: Gpi-anchor Cleavage Of Reck By Glycerophosphodiesterase 2 Inmentioning

confidence: 99%

GPI-AP release in cellular, developmental, and reproductive biology

Fujihara

Ikawa

2016

Journal of Lipid Research

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Male fertility is dependent on dipeptidase activity of testis ACE

Cited by 74 publications

References 10 publications

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

Angiotensin-Converting Enzyme C-Terminal Catalytic Domain Is the Main Site of Angiotensin I Cleavage In Vivo

Male accessory glands of Drosophila melanogaster make a secreted angiotensin I-converting enzyme (ANCE), suggesting a role for the peptide-processing enzyme in seminal fluid

GPI-AP release in cellular, developmental, and reproductive biology

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