Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
1999-11-15
2001-08-28
Achutamurthy, Ponnathapu (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C435S069100, C435S069700, C435S252300, C435S252330, C435S320100, C536S023200, C536S023400
Reexamination Certificate
active
06280994
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to a new protein expressed by human cells. In particular, the present invention relates to a novel gene that encodes a metalloenzyme, designated as “Zace1,” and to nucleic acid molecules encoding Zace1 polypeptides.
BACKGROUND OF THE INVENTION
Angiotensin-converting enzyme (ACE; peptidyl dipeptidase A; kininase II (EC 3.4.15.1)) is a zinc metallopeptidase that plays roles in blood pressure regulation and fertility. ACE is rather nonspecific and cleaves dipeptides from a broad range of substrates. In general, ACE cleaves a C-terminal dipeptide “A-B” from a polypeptide when A is not a proline residue, and B is neither an aspartate nor a glutamate residue. For example, ACE cleaves a single C-terminal dipeptide from angiotensin I to produce the potent vasopressor angiotensin II, and ACE cleaves the C-terminal dipeptide from [des-Asp
1
]angiotensin I to produce angiotensin III. The enzyme also inactivates the vasodilatory peptide bradykinin by sequential removal of two C-terminal dipeptides. For a general review of angiotensin-converting enzyme, see Corvol et al.,
Meth. Enzymol
. 246:283 (1995), Corvol et al.,
J. Hypertension
13(
Suppl
. 3):S3 (1995), Jackson and Garrison, “Renin and Angiotensin,”
in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics
, 9
th
Edition
, Molinoff and Ruddon (eds.), pages 733-758 (McGraw-Hill 1996), Matsusaka and Ichikawa,
Annu. Rev. Physiol
. 59:395 (1997), and Zimmerman and Dunham,
Annu. Rev. Pharmacol. Toxicol
. 37:53 (1997).
ACE is a cleavable ectoprotein anchored to the plasma membrane through a transmembrane domain. The majority of the membrane-bound form is extracellularly exposed, and this extracellular domain includes at least one active site. A soluble form of ACE circulates in plasma (see, for example, Hooper and Turner,
Biochem. Soc. Trans
., 17:660 (1989)).
Two ACE isoforms have been identified in mammalian tissues. The predominant form is referred to as “somatic” ACE, which has a molecular weight of about 150 kD to about 180 kD, and is predominantly found at the surface of vascular endothelial cells, epithelial cells, and neuroepithelial cells. The other isoform is referred to as “germinal” ACE or testis ACE (tACE), which has a molecular weight of about 90 kD to about 110 kD, and is expressed in post-meiotic cells and sperm. Human somatic ACE has two homologous domains, each comprising a catalytic site and a Zn
+2
-binding region, while human testis ACE contains one catalytic cite.
Hubert et al.,
J. Biol. Chem
. 266:15377 (1991), describe the complete intron-exon structure of the human ACE gene. The human ACE gene contains 26 exons, wherein exon 1 to exon 26 is transcribed in somatic ACE mRNA, but exon 13 is removed by splicing; germinal ACE mRNA is transcribed from exon 13 to exon 26. Exons 4-11 and 17-24 encode the two homologous domains (N domain and C domain) within somatic ACE, and are very similar in size and structure. The intron sizes are not conserved. Since somatic ACE and tACE are transcribed from a single gene, alternate splicing or alternative start sites for transcription initiation may be involved. Two functional promoters reside within the gene, which would support initiation from distinct start sites under separate control. The tACE promoter is upstream of the 5′ end of tACE mRNA, with a transcriptional initiation
Inhibitors of angiotensin-converting enzyme are used for the treatment of hypertension of various conditions, including left ventricular systolic dysfunction, progressive renal impairment, scleroderma renal crisis, congestive heart failure due to systolic dysfunction, and treatment of atherosclerosis (see, for example, Brown and Vaughan,
Circulation
97:1411 (1998); Mancini,
Am. J. Med
. 105:40S (1998); Parmley,
Am. J. Med
. 105:27S (1998)). There are at least nine ACE inhibitors approved for use in the United States.
ACE inhibitors can be classified into at least three groups: (1) sulfhydryl-containing inhibitors structurally related to captopril (e.g., fentiapril, pivalopril, zofenopril, alacepril), (2) dicarboxyl-containing inhibitors structurally related to enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril, spirapril, perindopril, indolapril, pentopril, indalapril, cilazapril), and (3) phosphorus-containing inhibitors structurally related to fosinopril. New classes of ACE inhibitors are sought that will inhibit ACE and other zinc metalloproteases. Moreover, new types of ACE inhibitors are also sought that will selectively inhibit ACE hydrolysis of N-acetyl-seryl-aspartyl-lysyl-prolyl (AcSDKP), a regulatory factor in hematopoiesis, without effect on angiotensin I or bradykinin metabolism.
Thus, a continuing need exists for the characterization of new forms of zinc metallopeptidases, and the use of the enzymes to identify therapeutically useful compounds.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a novel metallopeptidase, designated “Zace1.” The present invention also provides Zace1 polypeptides and Zace1 fusion proteins, nucleic acid molecules encoding such polypeptides and proteins, and methods for using these nucleic acid molecules and amino acid sequences.
REFERENCES:
patent: 5801040 (1998-09-01), Soubrier et al.
Lattion, A. L., et al., 1989, “The testicular transcript of the angiotensin I-converting enzyme encodes for the ancestral, non-duplicated form of the enzyme”, FEBS Letters, pp. 99-104.*
Ehlers, M. R. W., et al., 1989, “Molecular cloning of human testicular angiotensin-converting enzyme”, Proceedings of the National Academy of Sciences, U.S.A., vol. 86, pp. 7741-7745.*
T. Matsusaka and I. Ichikawa, “Biological Functions of Angiotensin and its Receptors,”Annu. Rev. Physiol.59:395-412 (1997).
H. Schunkert, “Polymorphism of the angiotensin-converting enzyme gene and cardiovascular disease,”J. Mol. Med75:867-875 (1997).
B. G. Zimmerman and E. W. Dunham, Tissue Renin-Angiotensin System: A Site of Drug Action?Annu. Rev. Pharmacol. Toxicol.37:53-69 (1997).
Achutamurthy Ponnathapu
Jones Phillip B. C.
Moore William W.
ZymoGenetics Inc.
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