Physiological Non-equivalence of the Two Isoforms of Angiotensin-converting Enzyme

Kessler, Sean P.; Rowe, T.; Gomos, Janette B.; Kessler, Patricia M.; Sen, Ganes C.

doi:10.1074/jbc.m004006200

Cited by 77 publications

(91 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S5 A-D). In sperm from WT mice, testicular angiotensin-converting enzyme (tACE), which is responsible for fertility (22)(23)(24), was located on the outer membrane of the acrosome, whereas it was ectopically localized on the plasma membrane of sperm from Ht mice (Fig. S5 E and F).…”

Section: Resultsmentioning

confidence: 99%

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

Takasaki

Tachibana

Ogasawara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

For normal fertilization in mammals, it is important that functionally mature sperm are motile and have a fully formed acrosome. The glycosyltransferase-like gene, human polypeptide N-acetylgalactosaminyltransferase-like protein 5 (GALNTL5), belongs to the polypeptide N-acetylgalactosamine-transferase (pp-GalNAc-T) gene family because of its conserved glycosyltransferase domains, but it uniquely truncates the C-terminal domain and is expressed exclusively in human testis. However, glycosyltransferase activity of the human GALNTL5 protein has not been identified by in vitro assay thus far. Using mouse Galntl5 ortholog, we have examined whether GALNTL5 is a functional molecule in spermatogenesis. It was observed that mouse GALNTL5 localizes in the cytoplasm of round spermatids in the region around the acrosome of elongating spermatids, and finally in the neck region of spermatozoa. We attempted to establish Galntl5-deficient mutant mice to investigate the role of Galntl5 in spermiogenesis and found that the heterozygous mutation affected male fertility due to immotile sperm, which is diagnosed as asthenozoospermia, an infertility syndrome in humans. Furthermore, the heterozygous mutation of Galntl5 attenuated glycolytic enzymes required for motility, disrupted protein loading into acrosomes, and caused aberrant localization of the ubiquitin-proteasome system. By comparing the protein compositions of sperm from infertile males, we found a deletion mutation of the exon of human GALNTL5 gene in a patient with asthenozoospermia. This strongly suggests that the genetic mutation of human GALNTL5 results in male infertility with the reduction of sperm motility and that GALNTL5 is a functional molecule essential for mammalian sperm formation.

show abstract

Section: Resultsmentioning

confidence: 99%

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

Takasaki

Tachibana

Ogasawara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Because the ACE modification involved point mutations impairing the zinc-binding properties of the N-terminal catalytic site, the tissue pattern of expression and the level of protein expression are no different from wild-type mice. This approach is different from that used by Kessler et al who created a transgenic mouse model in which rabbit testis ACE was expressed under the control of a tissue-specific promoter (Tie-1 or ␥-glutamyltransferase) in a background mouse strain that was null for the endogenous ACE gene (an ACE knock-out mouse (40)). Evaluation of ACE 7/7 mice showed that ACE enzymatic properties were consistent with our genetic design.…”

Section: Discussionmentioning

confidence: 99%

Role of the N-terminal Catalytic Domain of Angiotensin-converting Enzyme Investigated by Targeted Inactivation in Mice

Fuchs

Xiao

Cole

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Angiotensin-converting enzyme (ACE) produces the vasoconstrictor angiotensin II. The ACE protein is composed of two homologous domains, each binding zinc and each independently catalytic. To assess the physiologic significance of the two ACE catalytic domains, we used gene targeting in mice to introduce two point mutations (H395K and H399K) that selectively inactivated the ACE N-terminal catalytic site. This modification does not affect C-terminal enzymatic activity or ACE protein expression. In addition, the testis ACE isozyme is not affected by the mutations. Analysis of homozygous mutant mice (termed ACE 7/7) showed normal plasma levels of angiotensin II but an elevation of plasma and urine N-acetyl-Ser-Asp-Lys-Pro, a peptide suggested to inhibit bone marrow maturation. Despite this, ACE 7/7 mice had blood pressure, renal function, and hematocrit that were indistinguishable from wild-type mice. We also studied compound heterozygous mice in which one ACE allele was null (no ACE expression) and the second allele encoded the mutations selectively inactivating the N-terminal catalytic domain. These mice produced approximately half the normal levels of ACE, with the ACE protein lacking N-terminal catalytic activity. Despite this, the mice have a phenotype indistinguishable from wild-type animals. This study shows that, in vivo, the presence of the C-terminal ACE catalytic domain is sufficient to maintain a functional renin-angiotensin system. It also strongly suggests that the anemia present in ACE null mice is not due to the accumulation of the peptide N-acetyl-Ser-Asp-Lys-Pro.The major role of the renin-angiotensin system (RAS) 1 is the regulation of electrolyte homeostasis and blood pressure in mammals. The major effector peptide of the RAS is the octapeptide angiotensin II, which raises blood pressure through a variety of mechanisms, including vasoconstriction and the control of aldosterone release. Angiotensin II is the product of two successive enzymatic cleavages of angiotensinogen. First, renin releases the intermediate decapeptide angiotensin I. Then the last two C terminus amino acids of angiotensin I are removed by the zinc-metallopeptidase, angiotensin-converting enzyme (ACE) (1). ACE inhibitors markedly reduce the formation of angiotensin II and are widely used in the treatment of hypertension, congestive heart failure, and diabetic nephropathy.

show abstract

“…Male mice lacking calmegin (10,11), a testis-specific isoform of angiotensin-converting enzyme (tACE) (12,13), and ADAM2 (14) are all sterile because of the sperm defects in binding to the ZP and in migrating from the uterus into oviduct. Sperm from ADAM3-deficient mice are also defective in ZP binding but can ascend into the oviduct normally (15,16).…”

mentioning

confidence: 99%

Possible Function of the ADAM1a/ADAM2 Fertilin Complex in the Appearance of ADAM3 on the Sperm Surface

Nishimura¹,

Kim

Nakanishi

et al. 2004

Journal of Biological Chemistry

174

205

View full text Add to dashboard Cite

In mouse, two different isoforms of ADAM1 (fertilin ␣), ADAM1a and ADAM1b, are produced in the testis. ADAM1a is localized within the endoplasmic reticulum of testicular germ cells, whereas epididymal sperm contain only ADAM1b on the plasma membrane. In this study, we show that the loss of ADAM1a results in the male infertility because of the severely impaired ability of sperm to migrate from the uterus into the oviduct through the uterotubal junction. However, epididymal sperm of ADAM1a-deficient mice were capable of fertilizing cumulus-intact, zona pellucida-intact eggs in vitro despite the delayed dispersal of cumulus cells and the reduced adhesion/binding to the zona pellucida. Among testis (sperm)-specific proteins examined, only the level of ADAM3 (cyritestin) was strongly reduced in ADAM1a-deficient mouse sperm. Moreover, the appearance of ADAM3 on the sperm surface was dependent on the formation of a fertilin protein complex between ADAM1a and ADAM2 (fertilin ␤) in testicular germ cells, although no direct interaction between the fertilin complex and ADAM3 was found. These results suggest that ADAM1a/ADAM2 fertilin may be implicated in the selective transport of specific sperm proteins including ADAM3 from the endoplasmic reticulum of testicular germ cells onto the cell surface. These proteins then can participate in sperm migration into the oviduct, the dispersal of cumulus cells, and sperm binding to the zona pellucida.

show abstract

Physiological Non-equivalence of the Two Isoforms of Angiotensin-converting Enzyme

Cited by 77 publications

References 26 publications

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

A heterozygous mutation of GALNTL5 affects male infertility with impairment of sperm motility

Role of the N-terminal Catalytic Domain of Angiotensin-converting Enzyme Investigated by Targeted Inactivation in Mice

Possible Function of the ADAM1a/ADAM2 Fertilin Complex in the Appearance of ADAM3 on the Sperm Surface

Contact Info

Product

Resources

About