Transcription of Testicular Angiotensin-Converting Enzyme (ACE) Is Initiated within the 12th Intron of the Somatic ACE Gene

Abstract

Angiotensin-converting enzyme (ACE) is a zinc-containing dipeptidyl carboxypeptidase that catalyzes the conversion of angiotensin I to the potent vasoconstrictor angiotensin II. By analyzing cDNA and genomic DNA, we have constructed a consensus sequence encoding the testis isozyme of mouse ACE. Testis ACE cDNA contains 2,435 base pairs and encodes a protein of 732 amino acids. The N-terminal 66 amino acids are unique to the testis isozyme, while the remaining 666 are identical to the carboxyl half of mouse somatic ACE. The overall conservation of amino acid sequence between the testis isozymes of the mouse, rabbit, and human is 78 to 84%. The conservation of amino acids for the N-terminal domain uniquely expressed within the testis is 63 to 67% between these species. Primer extension and RNase protection experiments show that RNA transcription of the testis ACE isozyme begins 16 or 17 bases upstream from the translation start site. A sequence element resembling a TATA box is found 25 bases 5' of the transcription start site. To create its unique isozyme of ACE, the testis begins mRNA transcription in the middle of the exonic-intronic structure of somatic ACE, within a sequence treated as an intron by somatic tissues. Testis ACE is not the result of alternative RNA splicing but seems due to the start of transcription at a unique site within the ACE gene.

Angiotensin‐converting enzymes as druggable features of psychiatric and neurodegenerative disorders

“…sACE possesses two active sites (HEMGH motifs) responsible for the C-terminal processing of angiotensin peptides, notably including the conversion of Ang I to Ang II (Figure 3), with the subsequent activation of ATRs by Ang II, producing vasoconstriction and increasing the blood pressure (Wei et al, 1991). Through this function, sACE is considered to be the (Ehlers et al, 1989;Howard et al, 1990). Expression of ACE in the sperm is known to be essential for the fertility of mice, while mice that can express only tACE, and not sACE, remain fertile (Ramaraj et al, 1998).…”

“…A further genetic duplication event within ACE subsequently led to an expansion of this gene, giving it two alternative translational start sites. Depending on which of these start sites is used, two different isoenzymes of ACE can be translated, and these were named based on their expression pattern as somatic ACE (sACE) or testicular ACE (tACE; Howard et al, 1990). Therefore, three major ACE species exist in mammals: sACE, tACE, and ACE2 (Figure 3).…”

“…In contrast, little is known about the function of the alternative isoenzyme tACE (Khurana & Goswami, 2022; Turner & Nalivaeva, 2022). Expression of tACE occurs via an alternative promoter in intron 12 of the ACE gene, utilized only in testes, which encodes a shorter version of ACE, identical to the C‐terminal half of the sACE, but with a unique N‐terminal sequence, and with only one single HEMGH motif/active site (Ehlers et al, 1989; Howard et al, 1990). Expression of ACE in the sperm is known to be essential for the fertility of mice, while mice that can express only tACE, and not sACE, remain fertile (Ramaraj et al, 1998).…”

A Small Region in the Angiotensin-Converting Enzyme Distal Ectodomain Is Required for Cleavage-Secretion of the Protein at the Plasma Membrane

“…ACE exists as two isoforms, viz., somatic ACE (sACE), the larger isoform which is expressed mainly in the somatic tissues and the smaller isoform, germinal ACE (gACE), which is expressed in sperm cells. Both isoforms are synthesized from a single gene using tissue specific promoters and have distinct and specific functions in the body and they can not substitute for each other ,, . Both the isoforms of ACE are expressed on the cell surface as type I ectoprotein, with a long ectodomain, short cytoplasmic domain and a transmembrane domain – .…”

Assignment of Free and Disulfide-Bonded Cysteine Residues in Testis Angiotensin-Converting Enzyme: Functional Implications

“…The enzyme also inactivates the vasodilating peptide bradykinin. There are two isozymes of ACE that are encoded by the same gene but which are generated from different transcription initiation sites in a tissue-specific manner (Howard et al, 1990;Hubert et al, 1990). Somatic ACE, which is involved in blood pressure regulation, is an ectoprotein anchored to the membrane of endothelial, epithelial, and neuroepithelial cells.…”