An integrated computational and experimental study to increase the intra-cellular malonyl-CoA: Application to flavanone synthesis

Peng Xu, Sridhar Ranganathan, Costas D. Maranas, Mattheos Koffas

Research output: Chapter in Book/Report/Conference proceedingConference contribution

1 Citation (Scopus)

Abstract

Malonyl-coenzyme A is an important precursor metabolite for the biosynthesis of polyketides, fatty acids and biofuels. However, malonyl-CoA naturally synthesized in microbial hosts is consumed for the production of amino acids, fatty acids and phospholipids leaving behind only a small amount available for overproduction targets. During the past decade, computational procedures have aided many metabolic engineering efforts to design strains of bacteria and yeast that overproduce malonyl-CoA. In this regard, we present milestones achieved from an integrated computational and an experimental study aimed at improving the intracellular availability of malonyl-CoA in Escherichia coli. We deploy the recent OptForce methodology to predict a minimal set of genetic interventions that guarantees a pre-specified yield for malonyl-CoA in E. coli strain BL21 Star™. In order to validate the model predictions, we have successfully constructed a recombinant strain of E. coli that exhibits a 4-fold increase in the levels of intracellular malonyl-CoA compared to the wild-type strain. Furthermore, we demonstrate the applicability of this E. coli strain in the synthesis of plant-specific secondary metabolites (i.e., flavanones) that are promising agents in the treatment of cardiovascular disorders and diabetes. Specifically, a titer of 474 mg/L of naringenin production was observed which, so far, is the highest yield achieved in a lab-scale fermentation process.

Original languageEnglish (US)
Title of host publication2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011
DOIs
StatePublished - Jun 16 2011
Event37th Annual Northeast Bioengineering Conference, NEBEC 2011 - Troy, NY, United States
Duration: Apr 1 2011Apr 3 2011

Publication series

Name2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011

Other

Other37th Annual Northeast Bioengineering Conference, NEBEC 2011
CountryUnited States
CityTroy, NY
Period4/1/114/3/11

Fingerprint

Malonyl Coenzyme A
Escherichia coli
Metabolites
Fatty acids
Metabolic engineering
Coenzymes
Biosynthesis
Phospholipids
Fatty Acids
Biofuels
Medical problems
Flavanones
Yeast
Fermentation
Stars
Polyketides
Amino acids
Bacteria
Availability
flavanone

All Science Journal Classification (ASJC) codes

  • Bioengineering

Cite this

Xu, P., Ranganathan, S., Maranas, C. D., & Koffas, M. (2011). An integrated computational and experimental study to increase the intra-cellular malonyl-CoA: Application to flavanone synthesis. In 2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011 [5778699] (2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011). https://doi.org/10.1109/NEBC.2011.5778699
Xu, Peng ; Ranganathan, Sridhar ; Maranas, Costas D. ; Koffas, Mattheos. / An integrated computational and experimental study to increase the intra-cellular malonyl-CoA : Application to flavanone synthesis. 2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011. 2011. (2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011).
@inproceedings{8fed839dcc5648bd87d8dde4549f4fd0,
title = "An integrated computational and experimental study to increase the intra-cellular malonyl-CoA: Application to flavanone synthesis",
abstract = "Malonyl-coenzyme A is an important precursor metabolite for the biosynthesis of polyketides, fatty acids and biofuels. However, malonyl-CoA naturally synthesized in microbial hosts is consumed for the production of amino acids, fatty acids and phospholipids leaving behind only a small amount available for overproduction targets. During the past decade, computational procedures have aided many metabolic engineering efforts to design strains of bacteria and yeast that overproduce malonyl-CoA. In this regard, we present milestones achieved from an integrated computational and an experimental study aimed at improving the intracellular availability of malonyl-CoA in Escherichia coli. We deploy the recent OptForce methodology to predict a minimal set of genetic interventions that guarantees a pre-specified yield for malonyl-CoA in E. coli strain BL21 Star™. In order to validate the model predictions, we have successfully constructed a recombinant strain of E. coli that exhibits a 4-fold increase in the levels of intracellular malonyl-CoA compared to the wild-type strain. Furthermore, we demonstrate the applicability of this E. coli strain in the synthesis of plant-specific secondary metabolites (i.e., flavanones) that are promising agents in the treatment of cardiovascular disorders and diabetes. Specifically, a titer of 474 mg/L of naringenin production was observed which, so far, is the highest yield achieved in a lab-scale fermentation process.",
author = "Peng Xu and Sridhar Ranganathan and Maranas, {Costas D.} and Mattheos Koffas",
year = "2011",
month = "6",
day = "16",
doi = "10.1109/NEBC.2011.5778699",
language = "English (US)",
isbn = "9781612848273",
series = "2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011",
booktitle = "2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011",

}

Xu, P, Ranganathan, S, Maranas, CD & Koffas, M 2011, An integrated computational and experimental study to increase the intra-cellular malonyl-CoA: Application to flavanone synthesis. in 2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011., 5778699, 2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011, 37th Annual Northeast Bioengineering Conference, NEBEC 2011, Troy, NY, United States, 4/1/11. https://doi.org/10.1109/NEBC.2011.5778699

An integrated computational and experimental study to increase the intra-cellular malonyl-CoA : Application to flavanone synthesis. / Xu, Peng; Ranganathan, Sridhar; Maranas, Costas D.; Koffas, Mattheos.

2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011. 2011. 5778699 (2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011).

Research output: Chapter in Book/Report/Conference proceedingConference contribution

TY - GEN

T1 - An integrated computational and experimental study to increase the intra-cellular malonyl-CoA

T2 - Application to flavanone synthesis

AU - Xu, Peng

AU - Ranganathan, Sridhar

AU - Maranas, Costas D.

AU - Koffas, Mattheos

PY - 2011/6/16

Y1 - 2011/6/16

N2 - Malonyl-coenzyme A is an important precursor metabolite for the biosynthesis of polyketides, fatty acids and biofuels. However, malonyl-CoA naturally synthesized in microbial hosts is consumed for the production of amino acids, fatty acids and phospholipids leaving behind only a small amount available for overproduction targets. During the past decade, computational procedures have aided many metabolic engineering efforts to design strains of bacteria and yeast that overproduce malonyl-CoA. In this regard, we present milestones achieved from an integrated computational and an experimental study aimed at improving the intracellular availability of malonyl-CoA in Escherichia coli. We deploy the recent OptForce methodology to predict a minimal set of genetic interventions that guarantees a pre-specified yield for malonyl-CoA in E. coli strain BL21 Star™. In order to validate the model predictions, we have successfully constructed a recombinant strain of E. coli that exhibits a 4-fold increase in the levels of intracellular malonyl-CoA compared to the wild-type strain. Furthermore, we demonstrate the applicability of this E. coli strain in the synthesis of plant-specific secondary metabolites (i.e., flavanones) that are promising agents in the treatment of cardiovascular disorders and diabetes. Specifically, a titer of 474 mg/L of naringenin production was observed which, so far, is the highest yield achieved in a lab-scale fermentation process.

AB - Malonyl-coenzyme A is an important precursor metabolite for the biosynthesis of polyketides, fatty acids and biofuels. However, malonyl-CoA naturally synthesized in microbial hosts is consumed for the production of amino acids, fatty acids and phospholipids leaving behind only a small amount available for overproduction targets. During the past decade, computational procedures have aided many metabolic engineering efforts to design strains of bacteria and yeast that overproduce malonyl-CoA. In this regard, we present milestones achieved from an integrated computational and an experimental study aimed at improving the intracellular availability of malonyl-CoA in Escherichia coli. We deploy the recent OptForce methodology to predict a minimal set of genetic interventions that guarantees a pre-specified yield for malonyl-CoA in E. coli strain BL21 Star™. In order to validate the model predictions, we have successfully constructed a recombinant strain of E. coli that exhibits a 4-fold increase in the levels of intracellular malonyl-CoA compared to the wild-type strain. Furthermore, we demonstrate the applicability of this E. coli strain in the synthesis of plant-specific secondary metabolites (i.e., flavanones) that are promising agents in the treatment of cardiovascular disorders and diabetes. Specifically, a titer of 474 mg/L of naringenin production was observed which, so far, is the highest yield achieved in a lab-scale fermentation process.

UR - http://www.scopus.com/inward/record.url?scp=79958699598&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79958699598&partnerID=8YFLogxK

U2 - 10.1109/NEBC.2011.5778699

DO - 10.1109/NEBC.2011.5778699

M3 - Conference contribution

AN - SCOPUS:79958699598

SN - 9781612848273

T3 - 2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011

BT - 2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011

ER -

Xu P, Ranganathan S, Maranas CD, Koffas M. An integrated computational and experimental study to increase the intra-cellular malonyl-CoA: Application to flavanone synthesis. In 2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011. 2011. 5778699. (2011 IEEE 37th Annual Northeast Bioengineering Conference, NEBEC 2011). https://doi.org/10.1109/NEBC.2011.5778699