Tailoring enzymes involved in the biosynthesis of angucyclines contain latent context-dependent catalytic activities

Pekka Patrikainen; Pauli Kallio; Keqiang Fan; Karel D. Klika; Khaled A. Shaaban; Pekka Mäntsälä; Jürgen Rohr; Keqian Yang; Jarmo Niemi; Mikko Metsä-Ketelä

doi:10.1016/j.chembiol.2012.04.010

Tailoring enzymes involved in the biosynthesis of angucyclines contain latent context-dependent catalytic activities

Pekka Patrikainen, Pauli Kallio, Keqiang Fan, Karel D. Klika, Khaled A. Shaaban, Pekka Mäntsälä, Jürgen Rohr, Keqian Yang, Jarmo Niemi, Mikko Metsä-Ketelä

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

27 Scopus citations

Abstract

Comparison of homologous angucycline modification enzymes from five closely related Streptomyces pathways (pga, cab, jad, urd, lan) allowed us to deduce the biosynthetic steps responsible for the three alternative outcomes: gaudimycin C, dehydrorabelomycin, and 11-deoxylandomycinone. The C-12b-hydroxylated urdamycin and gaudimycin metabolites appear to be the ancestral representatives from which landomycins and jadomysins have evolved as a result of functional divergence of the ketoreductase LanV and hydroxylase JadH, respectively. Specifically, LanV has acquired affinity for an earlier biosynthetic intermediate resulting in a switch in biosynthetic order and lack of hydroxyls at C-4a and C-12b, whereas in JadH, C-4a/C-12b dehydration has evolved into an independent secondary function replacing C-12b hydroxylation. Importantly, the study reveals that many of the modification enzymes carry several alternative, hidden, or ancestral catalytic functions, which are strictly dependent on the biosynthetic context.

Original language	English
Pages (from-to)	647-655
Number of pages	9
Journal	Chemistry and Biology
Volume	19
Issue number	5
DOIs	https://doi.org/10.1016/j.chembiol.2012.04.010
State	Published - May 25 2012

Bibliographical note

Funding Information:
We thank Andriy Luzhetskyy and Andreas Bechthold for cosmid H2-26 and Streptomyces fradiae AO strain. This study was supported by the Academy of Finland (Grant 121688 to J.N., 127844 to P.M., and 136060 to M.M.-K.), the National Natural Science Foundation of China (Grant 31130001 to K.Y.), Turun Yliopistosäätiö (to K.D.K), and US National Institutes of Health (Grants CA091901 and CA102102 to J.R.). The Center for Scientific Computing is acknowledged for computational resources.

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

Access to Document

10.1016/j.chembiol.2012.04.010

Cite this

@article{94fa846c87814054bff224ee0ca472af,

title = "Tailoring enzymes involved in the biosynthesis of angucyclines contain latent context-dependent catalytic activities",

abstract = "Comparison of homologous angucycline modification enzymes from five closely related Streptomyces pathways (pga, cab, jad, urd, lan) allowed us to deduce the biosynthetic steps responsible for the three alternative outcomes: gaudimycin C, dehydrorabelomycin, and 11-deoxylandomycinone. The C-12b-hydroxylated urdamycin and gaudimycin metabolites appear to be the ancestral representatives from which landomycins and jadomysins have evolved as a result of functional divergence of the ketoreductase LanV and hydroxylase JadH, respectively. Specifically, LanV has acquired affinity for an earlier biosynthetic intermediate resulting in a switch in biosynthetic order and lack of hydroxyls at C-4a and C-12b, whereas in JadH, C-4a/C-12b dehydration has evolved into an independent secondary function replacing C-12b hydroxylation. Importantly, the study reveals that many of the modification enzymes carry several alternative, hidden, or ancestral catalytic functions, which are strictly dependent on the biosynthetic context.",

author = "Pekka Patrikainen and Pauli Kallio and Keqiang Fan and Klika, {Karel D.} and Shaaban, {Khaled A.} and Pekka M{\"a}nts{\"a}l{\"a} and J{\"u}rgen Rohr and Keqian Yang and Jarmo Niemi and Mikko Mets{\"a}-Ketel{\"a}",

note = "Funding Information: We thank Andriy Luzhetskyy and Andreas Bechthold for cosmid H2-26 and Streptomyces fradiae AO strain. This study was supported by the Academy of Finland (Grant 121688 to J.N., 127844 to P.M., and 136060 to M.M.-K.), the National Natural Science Foundation of China (Grant 31130001 to K.Y.), Turun Yliopistos{\"a}{\"a}ti{\"o} (to K.D.K), and US National Institutes of Health (Grants CA091901 and CA102102 to J.R.). The Center for Scientific Computing is acknowledged for computational resources. ",

year = "2012",

month = may,

day = "25",

doi = "10.1016/j.chembiol.2012.04.010",

language = "English",

volume = "19",

pages = "647--655",

number = "5",

}

TY - JOUR

T1 - Tailoring enzymes involved in the biosynthesis of angucyclines contain latent context-dependent catalytic activities

AU - Patrikainen, Pekka

AU - Kallio, Pauli

AU - Fan, Keqiang

AU - Klika, Karel D.

AU - Shaaban, Khaled A.

AU - Mäntsälä, Pekka

AU - Rohr, Jürgen

AU - Yang, Keqian

AU - Niemi, Jarmo

AU - Metsä-Ketelä, Mikko

N1 - Funding Information: We thank Andriy Luzhetskyy and Andreas Bechthold for cosmid H2-26 and Streptomyces fradiae AO strain. This study was supported by the Academy of Finland (Grant 121688 to J.N., 127844 to P.M., and 136060 to M.M.-K.), the National Natural Science Foundation of China (Grant 31130001 to K.Y.), Turun Yliopistosäätiö (to K.D.K), and US National Institutes of Health (Grants CA091901 and CA102102 to J.R.). The Center for Scientific Computing is acknowledged for computational resources.

PY - 2012/5/25

Y1 - 2012/5/25

N2 - Comparison of homologous angucycline modification enzymes from five closely related Streptomyces pathways (pga, cab, jad, urd, lan) allowed us to deduce the biosynthetic steps responsible for the three alternative outcomes: gaudimycin C, dehydrorabelomycin, and 11-deoxylandomycinone. The C-12b-hydroxylated urdamycin and gaudimycin metabolites appear to be the ancestral representatives from which landomycins and jadomysins have evolved as a result of functional divergence of the ketoreductase LanV and hydroxylase JadH, respectively. Specifically, LanV has acquired affinity for an earlier biosynthetic intermediate resulting in a switch in biosynthetic order and lack of hydroxyls at C-4a and C-12b, whereas in JadH, C-4a/C-12b dehydration has evolved into an independent secondary function replacing C-12b hydroxylation. Importantly, the study reveals that many of the modification enzymes carry several alternative, hidden, or ancestral catalytic functions, which are strictly dependent on the biosynthetic context.

AB - Comparison of homologous angucycline modification enzymes from five closely related Streptomyces pathways (pga, cab, jad, urd, lan) allowed us to deduce the biosynthetic steps responsible for the three alternative outcomes: gaudimycin C, dehydrorabelomycin, and 11-deoxylandomycinone. The C-12b-hydroxylated urdamycin and gaudimycin metabolites appear to be the ancestral representatives from which landomycins and jadomysins have evolved as a result of functional divergence of the ketoreductase LanV and hydroxylase JadH, respectively. Specifically, LanV has acquired affinity for an earlier biosynthetic intermediate resulting in a switch in biosynthetic order and lack of hydroxyls at C-4a and C-12b, whereas in JadH, C-4a/C-12b dehydration has evolved into an independent secondary function replacing C-12b hydroxylation. Importantly, the study reveals that many of the modification enzymes carry several alternative, hidden, or ancestral catalytic functions, which are strictly dependent on the biosynthetic context.

UR - http://www.scopus.com/inward/record.url?scp=84861598935&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861598935&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2012.04.010

DO - 10.1016/j.chembiol.2012.04.010

M3 - Article

C2 - 22633416

AN - SCOPUS:84861598935

SN - 1074-5521

VL - 19

SP - 647

EP - 655

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 5

ER -

Tailoring enzymes involved in the biosynthesis of angucyclines contain latent context-dependent catalytic activities

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this