Polynucleotide encoding a novel acyl coenzyme a, monoacylglycerol acyltransferase-3 (MGAT3), and uses thereof

• US 20040223959A1
• Filed: 01/21/2004
• Published: 11/11/2004
• Est. Priority Date: 01/21/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Chen, Jian, Feder, John N., Nelson, Thomas C., Ramaker, Michael, Meegalla, Rupalie, Cheng, Dong
• Granted Patent: US 7,259,002 B2
• Time in Patent Office: Days
• US Class Current: 424/94.5
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: C12N 9/1029 transferring groups other than amino-acyl groups (2.3.1)

Abstract

The present invention provides novel polynucleotides encoding MGAT3 polypeptides, fragments and homologues thereof. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing said polypeptides. The invention further relates to diagnostic and therapeutic methods for applying these novel MGAT3 polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders related to these polypeptides, such as obesity. The invention further relates to screening methods for identifying agonists and antagonists of the polynucleotides and polypeptides of the present invention.

Claims

1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence selected from the group consisting of:

(a) a polynucleotide fragment of SEQ ID NO;

1 or a polynucleotide fragment of the cDNA sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803, which is hybridizable to SEQ ID NO;

1;

(b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO;

2 or a polypeptide fragment encoded by the cDNA sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803, which is hybridizable to SEQ ID NO;

1;

(c) a polynucleotide encoding a polypeptide domain of SEQ ID NO;

2 or a polypeptide domain encoded by the cDNA sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803, which is hybridizable to SEQ ID NO;

1;

(d) a polynucleotide encoding a polypeptide epitope of SEQ ID NO;

2 or a polypeptide epitope encoded by the cDNA sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803, which is hybridizable to SEQ ID NO;

1;

(e) a polynucleotide encoding a polypeptide of SEQ ID NO;

2 or the cDNA sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803, which is hybridizable to SEQ ID NO;

1, having MGAT activity;

(f) a polynucleotide which is a variant of SEQ ID NO;

1;

(g) a polynucleotide which is an allelic variant of SEQ ID NO;

1;

(h) an isolated polynucleotide comprising nucleotides 171 to 1190 of SEQ ID NO;

1, wherein said nucleotides encode a polypeptide corresponding to amino acids 2 to 341 of SEQ ID NO;

2 minus the start methionine;

(i) an isolated polynucleotide comprising nucleotides 168 to 1190 of SEQ ID NO;

1, wherein said nucleotides encode a polypeptide corresponding to amino acids 1 to 341 of SEQ ID NO;

2 including the start codon;

a polynucleotide which represents the complimentary sequence (antisense) of SEQ ID NO;

1; and

(k) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(j), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.

2. A recombinant vector comprising said isolated nucleic acid molecule of claim 1.

3. A recombinant host cell comprising said recombinant vector of claim 2.

14. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:

(a) determining the presence or absence of a mutation in said polynucleotide of claim 1;

and

(b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.

4. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of:

(a) a polypeptide fragment of SEQ ID NO;

2 or the encoded sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803;

(b) a polypeptide fragment of SEQ ID NO;

2 or the encoded sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803, having MGAT activity;

(c) a polypeptide domain of SEQ ID NO;

2 or the encoded sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803;

(d) a polypeptide epitope of SEQ ID NO;

2 or the encoded sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803;

(e) a full length protein of SEQ ID NO;

2 or the encoded sequence included in at least one of ATCC Deposit No;

PTA-4454 or PTA-4803;

(f) a polypeptide comprising amino acids 2 to 341 of SEQ ID NO;

2, wherein said amino acids 2 to 341 comprising a polypeptide of SEQ ID NO;

2 minus the start methionine; and

(g) a polypeptide comprising amino acids 1 to 341 of SEQ ID NO;

2.

5. The isolated polypeptide of claim 4, wherein the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.

6. An isolated antibody that binds specifically to said isolated polypeptide of claim 4.

7. A recombinant host cell that expresses said isolated polypeptide of claim 4.

8. A method of making an isolated polypeptide comprising:

(a) culturing said recombinant host cell of claim 7 under conditions such that said polypeptide is expressed; and

(b) recovering said polypeptide.

9. The polypeptide produced by claim 8.

10. A method for preventing, treating, or ameliorating a medical condition, comprising the step of administering to a mammalian subject a therapeutically effective amount of said polypeptide of claim 4, or a modulator thereof.

11. A method of claim 10, wherein said medical condition is related to aberrant MGAT3 activity.

12. A method of claim 10, wherein said medical condition is selected from the group consisting of obesity and a gastrointestinal disorder.

13. A method of claim 12, wherein said gastrointestinal disorder is Crohn'"'"'s disease.

15. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:

(a) determining the presence or amount of expression of said polypeptide of claim 4 in a gastrointestinal tissue sample; and

(b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of said polypeptide.

16. A method of treating Crohn'"'"'s disease comprising administering to a patient in need thereof an MGAT3 polypeptide or a modulator thereof.