Structural characterization of CalO2: A putative orsellinic acid P450 oxidase in the calicheamicin biosynthetic pathway

Jason G. McCoy; Heather D. Johnson; Shanteri Singh; Craig A. Bingman; In Kyoung Lei; Jon S. Thorson; George N. Phillips

doi:10.1002/prot.22131

Structural characterization of CalO2: A putative orsellinic acid P450 oxidase in the calicheamicin biosynthetic pathway

Jason G. McCoy, Heather D. Johnson, Shanteri Singh, Craig A. Bingman, In Kyoung Lei, Jon S. Thorson, George N. Phillips

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Although bacterial iterative Type I polyketide synthases are now known to participate in the biosynthesis of a small set of diverse natural products, the subsequent downstream modification of the resulting polyketide products remains poorly understood. Toward this goal, we report the X-ray structure determination at 2.5 Å resolution and preliminary characterization of the putative orsellenic acid P450 oxidase (CalO2) involved in calicheamicin biosynthesis. These studies represent the first crystal structure for a P450 involved in modifying a bacterial iterative Type I polyketide product and suggest the CalO2-catalyzed step may occur after CalO3-catalyzed iodination and may also require a coenzyme A- (CoA) or acyl carrier protein- (ACP) bound substrate. Docking studies also reveal a putative docking site within CalO2 for the CLM orsellinic acid synthase (CalO5) ACP domain which involves a well- ordered helix along the CalO2 active site cavity that is unique compared with other P450 structures.

Original language	English
Pages (from-to)	50-60
Number of pages	11
Journal	Proteins: Structure, Function and Bioinformatics
Volume	74
Issue number	1
DOIs	https://doi.org/10.1002/prot.22131
State	Published - Jan 2009

Keywords

ACP
Biosynthesis
Natural product
Thioester
Type I PKS

ASJC Scopus subject areas

Structural Biology
Biochemistry
Molecular Biology

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10.1002/prot.22131

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title = "Structural characterization of CalO2: A putative orsellinic acid P450 oxidase in the calicheamicin biosynthetic pathway",

abstract = "Although bacterial iterative Type I polyketide synthases are now known to participate in the biosynthesis of a small set of diverse natural products, the subsequent downstream modification of the resulting polyketide products remains poorly understood. Toward this goal, we report the X-ray structure determination at 2.5 {\AA} resolution and preliminary characterization of the putative orsellenic acid P450 oxidase (CalO2) involved in calicheamicin biosynthesis. These studies represent the first crystal structure for a P450 involved in modifying a bacterial iterative Type I polyketide product and suggest the CalO2-catalyzed step may occur after CalO3-catalyzed iodination and may also require a coenzyme A- (CoA) or acyl carrier protein- (ACP) bound substrate. Docking studies also reveal a putative docking site within CalO2 for the CLM orsellinic acid synthase (CalO5) ACP domain which involves a well- ordered helix along the CalO2 active site cavity that is unique compared with other P450 structures.",

keywords = "ACP, Biosynthesis, Natural product, Thioester, Type I PKS",

author = "McCoy, {Jason G.} and Johnson, {Heather D.} and Shanteri Singh and Bingman, {Craig A.} and Lei, {In Kyoung} and Thorson, {Jon S.} and Phillips, {George N.}",

year = "2009",

month = jan,

doi = "10.1002/prot.22131",

language = "English",

volume = "74",

pages = "50--60",

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T2 - A putative orsellinic acid P450 oxidase in the calicheamicin biosynthetic pathway

AU - McCoy, Jason G.

AU - Johnson, Heather D.

AU - Singh, Shanteri

AU - Bingman, Craig A.

AU - Lei, In Kyoung

AU - Thorson, Jon S.

AU - Phillips, George N.

PY - 2009/1

Y1 - 2009/1

N2 - Although bacterial iterative Type I polyketide synthases are now known to participate in the biosynthesis of a small set of diverse natural products, the subsequent downstream modification of the resulting polyketide products remains poorly understood. Toward this goal, we report the X-ray structure determination at 2.5 Å resolution and preliminary characterization of the putative orsellenic acid P450 oxidase (CalO2) involved in calicheamicin biosynthesis. These studies represent the first crystal structure for a P450 involved in modifying a bacterial iterative Type I polyketide product and suggest the CalO2-catalyzed step may occur after CalO3-catalyzed iodination and may also require a coenzyme A- (CoA) or acyl carrier protein- (ACP) bound substrate. Docking studies also reveal a putative docking site within CalO2 for the CLM orsellinic acid synthase (CalO5) ACP domain which involves a well- ordered helix along the CalO2 active site cavity that is unique compared with other P450 structures.

AB - Although bacterial iterative Type I polyketide synthases are now known to participate in the biosynthesis of a small set of diverse natural products, the subsequent downstream modification of the resulting polyketide products remains poorly understood. Toward this goal, we report the X-ray structure determination at 2.5 Å resolution and preliminary characterization of the putative orsellenic acid P450 oxidase (CalO2) involved in calicheamicin biosynthesis. These studies represent the first crystal structure for a P450 involved in modifying a bacterial iterative Type I polyketide product and suggest the CalO2-catalyzed step may occur after CalO3-catalyzed iodination and may also require a coenzyme A- (CoA) or acyl carrier protein- (ACP) bound substrate. Docking studies also reveal a putative docking site within CalO2 for the CLM orsellinic acid synthase (CalO5) ACP domain which involves a well- ordered helix along the CalO2 active site cavity that is unique compared with other P450 structures.

KW - ACP

KW - Biosynthesis

KW - Natural product

KW - Thioester

KW - Type I PKS

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SN - 0887-3585

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JO - Proteins: Structure, Function and Bioinformatics

JF - Proteins: Structure, Function and Bioinformatics

IS - 1

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Structural characterization of CalO2: A putative orsellinic acid P450 oxidase in the calicheamicin biosynthetic pathway

Abstract

Keywords

ASJC Scopus subject areas

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