IP Library › Granted Patent US 12,215,368
Granted Patent B2
US 12,215,368 · App. 17/600,345 · Granted Feb 4, 2025

Engineered imine reductases and methods for the reductive amination of ketone and amine compounds

Inventors: Xiang Yi (San Carlos, CA); Oscar Alvizo (Fremont, CA); Ravi David Garcia (Los Gatos, CA); David Entwistle (San Carlos, CA); Charlene Ching (San Jose, CA); James Nicholas Riggins (San Francisco, CA)
Assignee: Codexis, Inc.
C12P13/04C12N9/0028
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Quick Facts
Patent No.
US 12,215,368
App. No.
17/600,345
Granted
Feb 4, 2025
Kind
B2
Abstract

The present application provides engineered polypeptides having imine reductase activity, polynucleotides encoding the engineered polypeptides, host cells capable of expressing the engineered polypeptides, and methods of using these engineered polypeptides with a range of ketone and amine substrate compounds to prepare secondary and tertiary amine product compounds.

Claims (34)

1. An engineered polypeptide having imine reductase activity and comprising an amino acid sequence with at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 4, wherein the tyrosine at the position corresponding to amino acid 222 of SEQ ID NO: 4 is substituted with another amino acid in the sequence of the engineered polypeptide.

2. The engineered polypeptide of claim 1 , further comprising at least one substitution or substitution set as compared to the amino acid sequence of SEQ ID NO: 4, wherein the at least one substitution or substitution set is at one or more positions selected from 29/94/184/223/232/288/293, 29/94/184/232/287/288/293/311, 29/94/184/232/287/288/311, 29/94/184/232/287/293/332, 29/94/184/232/288/293/311/324/353, 29/94/184/232/288/311/324/332, 29/94/184/232/293, 29/94/184/232/311, 29/94/184/287/293, 29/94/184/287/293/311/353, 29/94/184/287/311, 29/94/184/288/293/324, 29/94/184/288/293/332/353, 29/94/184/288/298/332, 29/94/184/288/353, 29/94/184/293/311, 29/94/184/324, 29/94/223/232/287, 29/94/223/232/293/311/324, 29/94/223/288/293, 29/94/232/287/288/311, 29/94/232/288/293, 29/94/287/288/293, 29/94/287/288/293/353, 29/94/287/311, 29/94/293/311/324, 29/94/293/332/353, 29/94/311, 29/94/324/353, 29/184, 29/184/223/288/293/324, 29/184/232/288, 29/184/287, 29/184/287/288/293, 29/184/287/288/293/311, 29/184/287/311/332, 29/184/288/293, 29/184/288/293/311, 29/184/293, 29/184/293/311, 29/184/293/324, 29/184/353, 29/223/287/288/293/353, 29/232/287/288/293/332/353, 29/287/288/293, 29/287/288/293/324/353, 29/288/293, 29/311, 29/311/332, 29/353, 72/94/184/288/311, 86, 94/96/223/287/288/293/311/324/332, 94/99/184/293/311/332/353, 94/184/223, 94/184/223/232/287/311, 94/184/223/288/293, 94/184/223/293, 94/184/232/287/288, 94/184/232/287/288/324/332, 94/184/232/287/293, 94/184/232/287/293/332, 94/184/287/288/293, 94/184/287/288/311, 94/184/287/293/311/324/353, 94/184/287/311, 94/184/287/353, 94/184/288/293, 94/184/288/293/311, 94/184/288/293/311/332, 94/184/293, 94/184/293/311, 94/184/293/332/353, 94/223/232/311/353/355/356/357/358/359, 94/223/287/288/293, 94/223/288/293/311, 94/232/287/288/293/353, 94/232/288/293/353, 94/232/293, 94/232/293/324/332, 94/232/311, 94/287/288/293, 94/287/288/311/324, 94/288/293, 94/288/293/324, 94/293/324, 94/311/324, 153, 184/223, 184/223/287/288/353, 184/232/287/288/293/311, 184/232/287/288/324/353, 184/232/287/293/332, 184/287/288, 184/287/288/293, 184/287/288/293/324/353, 184/287/293, 184/287/293/311, 184/288/293/311/324, 184/332/353, 205, 223/232/287/288/332/353, 223/287/288, 223/287/288/293/311, 223/287/311/353, 223/288/293, 232/287/288/293, 232/287/288/293/311, 232/287/288/293/321, 232/287/311, 232/288/293, 232/288/293/332, 234/287/288/293/311, 287/288/293, 287/288/311/324, 287/293, 287/311, 287/311/332, 287/324, 288/293, 288/293/311/324/353, 288/293/324, 293/311, and 311/332.

3. The engineered polypeptide of claim 1 , further comprising at least one substitution or substitution set as compared to the amino acid sequence of SEQ ID NO: 4, wherein the at least one substitution or substitution set is at one or more positions selected from 29/57/94/153/184/205/261/265/287, 29/57/94/153/205/265, 29/57/94/184/205/277/353, 29/57/94/205/259/261/265, 29/57/94/205/261/353, 29/57/153/184/205/259/261/265/277, 29/57/153/184/205/353, 29/57/153/205/261/265, 29/57/153/205/261/265/277, 29/57/153/205/265/277, 29/57/153/205/277/353, 29/57/184/205/259/261/265/277/287/357, 29/57/184/205/259/261/265/287, 29/57/205/259/261/265, 29/57/205/259/261/265/287, 29/57/205/261/265/353, 29/94/153/184/205, 29/94/153/205/259/261/265, 29/94/153/205/259/261/287, 29/94/153/205/259/261/287/353, 29/94/184/205/259/261, 29/94/184/205/261, 29/94/205, 29/94/205/259/261/287, 29/94/205/261, 29/94/261/265/287/353, 29/153/184/205, 29/153/205, 29/153/205/259/261/265/277/287, 29/153/261/265/287/353, 29/184/205, 29/184/205/259/261/277, 29/184/205/353, 29/184/261/265, 29/184/265, 29/205, 29/205/259/261, 29/205/259/261/265/287, 29/205/259/261/287, 29/205/261, 29/205/261/265, 29/205/261/265/353, 29/205/261/353, 29/205/277, 29/205/287, 29/205/287/353, 29/259/261/265, 29/261/353, 57/94/153/184/205/259/261, 57/94/153/205/261/265, 57/94/153/259/261/265, 57/94/153/261/265, 57/94/184/205/261/265/287, 57/94/184/261/265/287, 57/94/205/259, 57/94/205/259/261/265/277/287, 57/94/205/261/265, 57/94/205/277, 57/153/205/259/261/265/287, 57/153/205/259/265/277, 57/153/205/261, 57/153/205/261/265, 57/153/205/265, 57/153/261/265, 57/153/261/265/287/353, 57/205, 57/205/259/261, 57/205/259/261/265/277/287/353, 57/205/259/261/287/353, 57/205/259/265, 57/205/261, 57/205/261/265/277/287/353, 57/205/261/277, 57/205/261/277/353, 57/261/265/353, 94/126/184/205/259/261/265, 94/153/184/205, 94/153/184/259/261/265, 94/153/205/259/261/265/353, 94/153/205/287, 94/153/205/287/353, 94/153/205/353, 94/184/205/259/261, 94/184/205/259/261/265/287, 94/184/205/259/261/353, 94/184/205/261/265/287/353, 94/184/353, 94/205, 94/205/259/261/265, 94/205/259/261/265/277/287, 94/205/259/261/265/353, 94/205/259/261/287/353, 94/205/261/265/277, 94/205/261/265/353, 94/205/261/353, 94/205/277, 94/259/261/265, 153/184/205/261/277/287, 153/184/261/265/287, 153/205, 153/205/261, 153/205/261/265/287, 153/259/261/265, 153/259/265/287, 153/261/265, 153/261/265/287/353, 153/265, 153/265/277/287/353, 184/205, 184/205/259/261/287, 184/205/261, 184/205/261/265, 184/205/261/287, 184/205/277, 184/205/287/353, 184/261/265/287, 202, 205, 205/259/261, 205/259/261/265, 205/259/261/265/277/287/353, 205/259/261/277/287, 205/259/265, 205/261, 205/261/265, 205/261/265/274, 205/261/265/287, 205/261/265/287/353, 205/261/277, 205/261/353, 205/277/287, 205/287, 223, 225, 256, 259/261/265, 261/265/287, 265/287, 283, and 294.

4. The engineered polypeptide of claim 1 , further comprising at least one substitution or substitution set as compared to the amino acid sequence of SEQ ID NO: 4, wherein the at least one substitution or substitution set is at one or more positions selected from 197/198/201/259, 198/201/259/280, 202/205/221/223/225/261, 202/205/221/223/261/294, 202/221/225/256/261/294, 202/221/223/225/283/294, 205/221, 205/221/223/225/256/261/283, 219, 221/223/225, 221/223, 221/223/225, 221/223/225/256/261, 221/223/225/261, 221/223/225/294, 221/225, 221/225/256, 221/225/256/261, 221/225/256/261/283/294, 223/225/256/261, 225/256/261, 280, and 280/306.

5. The engineered polypeptide of claim 1 , further comprising at least one substitution or substitution set as compared to the amino acid sequence of SEQ ID NO: 4, wherein the at least one substitution or substitution set is at one or more positions selected from 17/198/259/280, 197, 197/198, 197/198/223/259, 197/223/277/280, 197/259, 197/277, 198, 198/223, 198/223/259/277/280, 198/259, 198/259/277, 198/259/277/280, 198/277/280, 223/259, 223/259/280, 258, 259, 259/268/277/280, 259/277, 259/280, 263, 277, and 280.

6. The engineered polypeptide of claim 1 , further comprising at least one substitution or substitution set as compared to the amino acid sequence of SEQ ID NO: 4, wherein the at least one substitution or substitution set is at one or more positions selected from 141, 154, 197, 197/198, and 278.

7. The engineered polypeptide of claim 1 , wherein said engineered polypeptide comprises the amino acid sequence of SEQ ID NO: 16, 50, 306, 648 or 708.

8. The engineered polypeptide of claim 1 , wherein said polypeptide comprises an amino acid sequence with at least 90% sequence identity to an even-numbered sequence-selected from the group consisting of SEQ ID NO: 14, 16, 38-646, 650-684, 688-700, and 704-802.

9. The engineered polypeptide of claim 1 , wherein said engineered polypeptide comprises an amino acid sequence set forth in an even numbered sequence selected from the group consisting of SEQ ID NO: 14, 16, 38-646, 650-684, 688-700, and 704-802.

10. The engineered polypeptide of claim 1 , wherein said engineered polypeptide exhibits an improved property compared to the engineered polypeptide of SEQ ID NO: 4, wherein the improved property comprises improved production of a compound of structural Formula (IV)

wherein

R 1 is selected from a hydrogen atom, or optionally substituted alkyl, alkenyl, alkynyl, alkoxy, arylalkoxy, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, alkylthioalkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; and wherein

R 2 is independently selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxy, aminocarbonyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carboxyalkyl, alkylamino, haloalkyl, alkylthioalkyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl; and wherein

R 3 is independently selected from methyl, D 3 -methyl and ethyl.

11. The engineered polypeptide of claim 10 , wherein said improved property comprises improved production of compound (1)

12. The engineered polypeptide of claim 1 , wherein said engineered polypeptide exhibits an improved property compared to the engineered polypeptide of SEQ ID NO: 4, wherein the improved property comprises improved utilization of compound (2)

13. The engineered polypeptide of claim 1 , wherein said engineered polypeptide exhibits an improved property compared to the engineered polypeptide of SEQ ID NO: 4, wherein the improved property comprises improved utilization of compound (3)

14. The engineered polypeptide of claim 1 , wherein said engineered polypeptide exhibits an improved property compared to the engineered polypeptide of SEQ ID NO: 4, wherein the improved property comprises improved production of compound (1)

from compound (2)

and compound (3)

15. The engineered polypeptide of claim 1 , wherein said engineered polypeptide exhibits an improved property compared to the engineered polypeptide of SEQ ID NO: 4, wherein the improved property comprises improved conversion of one or more of conversion reactions selected from the group consisting of

(A) conversion of compounds

to the amine product compound

(B) the conversion of compounds

to the amine product compound

(C) the conversion of compounds

to the amine product compound

(D) the conversion of compounds

to the amine product compound

and

(E) the conversion of compounds

to the amine product compound

16. The engineered polypeptide of claim 1 , wherein said engineered polypeptide is purified.

17. A composition comprising the polypeptide of claim 1 .

Assignments (3)
SECURITY INTEREST Recorded Feb 15, 2024
From: CODEXIS, INC.
To: INNOVATUS LIFE SCIENCES LENDING FUND I, LP, AS COLLATERAL AGENT
Reel/Frame 066600/0650 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 9, 2024
From: YI, XIANG; RIGGINS, JAMES NICHOLAS; ALVIZO, OSCAR; GARCIA, RAVI DAVID; ENTWISTLE, DAVID; CHING, CHARLENE
To: CODEXIS, INC.
Reel/Frame 066425/0041 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 8, 2024
From: YI, XIANG; ALVIZO, OSCAR; GARCIA, RAVI DAVID; ENTWISTLE, DAVID; CHING, CHARLENE; RIGGINS, JAMES NICHOLAS
To: CODEXIS, INC.
Reel/Frame 066420/0322 →
Continuity (2)
Provisional Application 62841633 · May 1, 2019
Related Publication 20220213518A1 · Jul 7, 2022
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