Process for producing HMG-CoA reductase inhibitor

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Quick Facts

Patent No.: US 7,049,111
App. No.: 09/869,334
Granted: May 23, 2006
Kind: B1

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Abstract

The present invention relates to a protein derived from a microorganism belonging to the genus Bacillus , which has an activity of hydroxylating a compound represented by the formula (I-a): wherein R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl, or an alkali metal, and R 2 represents a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, or a ring-closed lactone form thereof; a DNA encoding the protein; and a recombinant DNA comprising the DNA.

Claims (67)

1. An isolated DNA having the nucleotide sequence shown by SEQ ID NO: 2.

2. A recombinant DNA vector comprising the DNA according to claim 1 .

3. An isolated transformed cell obtained by introducing the recombinant DNA vector according to claim 2 into a host cell.

4. The transformed cell according to claim 3 wherein the transformed cell belongs to a microorganism selected from the genera Escherichia, Bacillus, Corynebacterium , and Streptomyces.

5. The transformed cell according to claim 3 wherein the transformed cell belongs to microorganism selected from Escherichia coli, Bacillus subtilis, Bacillus megaterium, Corynebacterium glutamicum, Corynebacterium ammoniagenes, Corynebacterium callunae and Streptomyces lividans.

6. A process for producing compound (II-a) or compound (II-b), wherein The transformed cell according to claim 3 , a culture of the transformed cell, or a treated product of the culture is used as an enzyme source, and the process comprises:

allowing compound (I-a) or compound (I-b) to exist in an aqueous medium in the presence of the enzyme source;

allowing compound (II-a) or compound (II-b) to be produced and accumulated in said aqueous medium; and

collecting compound (II-a) or compound (II-b) from said aqueous medium wherein, the compound (I-a) is a compound represented by the formula (I-a):

the compound (I-b) is a lactone form of compound (I-a) and is represented by the formula (I-b):

the compound (II-a) is a compound represented by the formula (II-a):

the compound (II-b) is a lactone form of compound (II-a) and is represented by the formula (II-b):

and wherein R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl, or an alkali metal, and R 2 represents a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; and wherein the treated product of the culture of the transformed cell is a treated product selected from cultured cells, dried cells, freeze-dried cells, cells treated with a surfactant, cells treated with an enzyme, cells treated by ultrasonication, cells treated by mechanical milling, cells treated by solvent, a protein fraction of a cell, and immobilized cells.

7. A process for producing compound (IV-a) or compound (IV-b), wherein the transformed cell according to claim 3 , a culture of the transformed cell, or a treated product of the culture is used as an enzyme source, and the process comprises:

allowing compound (III-a) or compound (III-b) to exist in an aqueous medium in the presence of the enzyme source;

allowing compound (IV-a) or compound (IV-b) to be produced and accumulated in said aqueous medium; and

collecting compound (IV-a) or compound (IV-b) from said aqueous medium wherein, the compound (III-a) is a compound represented by the formula (III-a):

the compound (III-b) is a lactone form of compound (III-a) and is represented by the formula (III-b):

the compound (IV-a) is a compound represented by the formula (IV-a):

the compound (IV-b) is a lactone form of compound (IV-a) and is represented by the formula (IV-b):

8. A process for producing compound (VI-a) or compound (VI-b), wherein the transformed cell according to claim 3 , a culture of the transformed cell, or a treated product of the culture is used as an enzyme source, and the process comprises:

allowing compound (V-a) or compound (V-b) to exist in an aqueous medium in the presence of the enzyme source;

allowing compound (VI-a) or compound (VI-b) to be produced and accumulated in said aqueous medium; and

collecting compound (VI-a) or compound (VI-b) from said aqueous medium wherein, the compound (V-a) is a compound represented by the formula (V-a):

the compound (V-b) is a lactone form of compound (V-a) and is represented by the formula (V-b):

the compound (VI-a) is a compound represented by the formula (VI-a):

the compound (VI-b) is a lactone form of compound (VI-a) and is represented by the formula (VI-b):

and wherein R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl, or an alkali metal; and wherein the treated product of the culture of the transformed cell is a treated product selected from cultured cells, dried cells, freeze-dried cells, cells treated with a surfactant, cells treated with an enzyme, cells treated by ultrasonication, cells treated by mechanical milling, cells treated by solvent, a protein fraction of a cell, and immobilized cells.

9. A process for producing compound (VIII-a) or compound (VIII-b), wherein the transformed cell according to claim 3 , a culture of the transformed cell, or a treated product of the culture is used as an enzyme source, and the process comprises:

allowing compound (VII-a) or compound (VII-b) to exist in an aqueous medium in the presence of the enzyme source;

allowing compound (VII-a) or compound (VII-b) to be produced and accumulated in said aqueous medium; and

collecting compound (VIII-a) or compound (VIII-b) from said aqueous medium wherein, the compound (VII-a) is a compound represented by the formula (VII-a):

the compound (VII-b) is a lactone form of compound (VII-a) and is represented by the formula (VII-b):

the compound (VIII-a) is a compound represented by the formula (VIII-a):

the compound (VII-b) is a lactone form of compound (VIII-a) and is represented by the formula (VIII-b):

10. The process according to claim 6 , wherein the compound (II-b) is obtained by forming a lactone from compound (II-a), the compound (II-a) is a compound represented by the formula (II-a):

the compound (II-b) is a lactone form of compound (II-a) and is represented by the formula (II-b):