Improved Synthesis of Flavonoids by Simulation of Nargenine Chalcone Biosynthetic Reaction
Current Journal of Applied Science and Technology,
Metabolic Control Analysis provides a quantitative description of concentration dynamics with the change in system parameters. A metabolic Control Analysis aids determination of the threshold value of metabolites involved in a reaction and also helps to understand the role of various parameters in a reaction. In this work, a metabolic model of a Naringenine chalcone biosynthetic reaction is defined and a time series simulation was carried out based on the law of Mass action. Initial concentration of p-Coumaroyl-CoA and Malonyl-CoA were taken 5.0*10-2 mM 2.2*10-3 mM respectively. This concentration was then simulated over time for 10 seconds to find the steady state. Final concentration of Naringenine chalcone,CO2, and CoA becomes 8.593946e-004 mM after 5.00 second of simulation at reaction constant 6.587753e-005 mM*ml/s. Steady state solution shows that Initial concentration of Naringenine chalcone was 2.199777e-003 mM which is eventually converted into 2.785128e+013 seconds half-life concentration of product at 7.898e-017 mM/s rate and 0.000000e+000 mM*ml/s rate constant. Phenylpropanoid pathway was analysed to predict all the enzymes that can maximise and minimise the concentration of Malonyl-CoA and P-Coumaroyl-CoA which leads to flavonoid biosynthesis. In the Phenylpropanoid pathway four enzymes Phenylalanine/tyrosine ammonia lyase, trans-cinnamate 4-monooxygenase, Phenylalanine ammonia lyase, maximise the flavonoid biosynthesis. This analysis shows that other enzymes minimise the concentrations of Malonyl-CoA and P-coumaroyl-CoA, these are Cinnamoyl Co A reductase, shikimate O hydroxyl transferase HCT), Oxidoreductase. Furthermore, Protein domain analysis of chalcone synthase mutants ( 1jwx Medicago sativa and 4yjy from Oryza sativa) was done to predict structural features to understand reaction mechanism and structure-based engineering to maximise flavonoid biosynthesis. Natural sequence variation CHS G256A, G256V, G256L, and G256F mutants of residue 256 reduce the size of the active site cavity but quick diversification of product specificity occurs. The threshold concentration of Malonyl-CoA and P-coumaroyl-CoA were predicted, maximisation of this concentration leads to enhanced flavonoid biosynthesis. Inhibition of few enzymes may also maximise the flavonoid biosynthesis if appropriate inhibitors are used and a constant supply of Malonyl-CoA and P-Coumaroyl-CoA is maintained using activator molecules. Chalcone synthase Mutants diversify product specificity that occurs without loss of catalytic activity and any conformational changes.
- Naringenine chalcone
- phenylpropanoid pathway
- flavonoid biosynthesis
- metabolic control analysis.
How to Cite
Risdian C, Mozef T, Wink J. Biosynthesis of Polyketides in Streptomyces. Microorganisms [Internet]. 2019 May 6 [cited 2020 Nov 3];7(5). Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560455/
Lussier F-X, Colatriano D, Wiltshire Z, Page JE, Martin VJJ. Engineering Microbes for Plant Polyketide Biosynthesis. Comput Struct Biotechnol J [Internet]. 2013 Feb 22 [cited 2020 Nov 3];3. Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962132/
Pandith SA, Ramazan S, Khan MI, Reshi ZA, Shah MA. Chalcone synthases (CHSs): The symbolic type III polyketide synthases. Planta. 2019;251(1):15.
Yu D, Xu F, Zeng J, Zhan J. Type III polyketide synthases in natural product biosynthesis. IUBMB Life. 2012;64(4):285–95.
Lim YP, Go MK, Yew WS. Exploiting the Biosynthetic Potential of Type III Polyketide Synthases. Molecules [Internet]. 2016[cited 2020 Nov 3];21(6). Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274091/
Taura F, Iijima M, Yamanaka E, Takahashi H, Kenmoku H, Saeki H, et al. A Novel Class of Plant Type III Polyketide Synthase Involved in Orsellinic Acid Biosynthesis from Rhododendron dauricum. Front Plant Sci [Internet]. 2016 Sep 27 [cited 2020 Nov 3];7. Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037138/
Tzin V, Galili G. The Biosynthetic Pathways for Shikimate and Aromatic Amino Acids in Arabidopsis thaliana. Arabidopsis Book [Internet]. 2010 May 17 [cited 2020 Nov 3];8. Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244902/
Liang J, Luo Y, Zhao H. Synthetic biology: Putting synthesis into biology. Wiley Interdiscip Rev Syst Biol Med. 2011;3(1): 7–20.
Pearsall SM, Rowley CN, Berry A. Advances in Pathway Engineering for Natural Product Biosynthesis. ChemCatChem. 2015;7(19):3078–93.
Farré G, Blancquaert D, Capell T, Van Der Straeten D, Christou P, Zhu C. Engineering Complex Metabolic Pathways in Plants. Annual Review of Plant Biology. 2014;65(1):187–223.
Winter JM, Tang Y. Synthetic Biological Approaches to Natural Product Biosynthesis. Curr Opin Biotechnol. 2012; 23(5):736–43.
Wilkinson B, Micklefield J. Mining and engineering natural-product biosynthetic pathways. Nature Chemical Biology. 2007;3(7):379–86.
Lechner A, Brunk E, Keasling JD. The Need for Integrated Approaches in Metabolic Engineering. Cold Spring Harb Perspect Biol [Internet]. 2016 Nov [cited 2020 Nov 3];8(11). Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088530/
Kim OD, Rocha M, Maia P. A Review of Dynamic Modeling Approaches and Their Application in Computational Strain Optimization for Metabolic Engineering. Front Microbiol [Internet]; 2018. [cited 2020 Nov 3];9. Available:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079213/
Fukuma K, Neuls ED, Ryberg JM, Suh D-Y, Sankawa U. Mutational Analysis of Conserved Outer Sphere Arginine Residues of Chalcone Synthase. J Biochem. 2007;142(6):731–9.
Jez JM, Bowman ME, Noel JP. Structure-Guided Programming of Polyketide Chain-Length Determination in Chalcone Synthase. Biochemistry. 2001;40(49): 14829–38.
Go MK, Wongsantichon J, Cheung VWN, Chow JY, Robinson RC, Yew WS. Synthetic Polyketide Enzymology: Platform for Biosynthesis of Antimicrobial Polyketides. ACS Catal. 2015;5(7):4033–42.
Heller W, Hahlbrock K. Highly purified “flavanone synthase” from parsley catalyses the formation of naringenin chalcone. Archives of Biochemistry and Biophysics. 1980;200(2):617–9.
Yahyaa M, Ali S, Davidovich-Rikanati R, Ibdah M, Shachtier A, Eyal Y, et al. Characterization of three chalcone synthase-like genes from apple (Malus x domestica Borkh.). Phytochemistry. 2017; 140:125–33.
DELANO WL. The PyMOL Molecular Graphics System. http://www.pymol.org [Internet]; 2002. [cited 2020 Nov 11] Available:https://ci.nii.ac.jp/naid/10020095229/
Cascante M, Boros LG, Comin-Anduix B, de Atauri P, Centelles JJ, Lee PW-N. Metabolic control analysis in drug discovery and disease. Nature Biotechnology. 2002;20(3):243–9.
Raharjo TJ, Chang W-T, Choi YH, Peltenburg-Looman AMG, Verpoorte R. Olivetol as product of a polyketide synthase in Cannabis sativa L. Plant Science. 2004;166(2):381–5.
Dao TTH, Linthorst HJM, Verpoorte R. Chalcone synthase and its functions in plant resistance. Phytochem Rev. 2011; 10(3):397–412.
Nair RB, Bastress KL, Ruegger MO, Denault JW, Chapple C. The Arabidopsis thaliana REDUCED EPIDERMAL FLUORESCENCE1 Gene Encodes an Aldehyde Dehydrogenase Involved in Ferulic Acid and Sinapic Acid Biosynthesis. Plant Cell. 2004;16(2):544–54.
Baucher M, Halpin C, Petit-Conil M, Boerjan W. Lignin: Genetic engineering and impact on pulping. Crit Rev Biochem Mol Biol. 2003;38(4):305–50.
Rogers LA, Dubos C, Cullis IF, Surman C, Poole M, Willment J, et al. Light, the circadian clock, and sugar perception in the control of lignin biosynthesis. J Exp Bot. 2005;56(416):1651–63.
Xu P, Ranganathan S, Fowler ZL, Maranas CD, Koffas MAG. Genome-scale metabolic network modeling results in minimal interventions that cooperatively force carbon flux towards malonyl-CoA. Metab Eng. 2011;13(5):578–87.
Leonard E, Lim K-H, Saw P-N, Koffas MAG. Engineering central metabolic pathways for high-level flavonoid production in Escherichia coli. Appl Environ Microbiol. 2007;73(12):3877–86.
Leonard E, Yan Y, Fowler ZL, Li Z, Lim C-G, Lim K-H, et al. Strain Improvement of Recombinant Escherichia coli for Efficient Production of Plant Flavonoids. Mol Pharmaceutics. 2008;5(2):257–65.
Wu J, Yu O, Du G, Zhou J, Chen J. Fine-Tuning of the Fatty Acid Pathway by Synthetic Antisense RNA for Enhanced (2S)-Naringenin Production from l-Tyrosine in Escherichia coli. Appl Environ Microbiol. 2014;80(23):7283–92.
Cronan JE, Waldrop GL. Multi-subunit acetyl-CoA carboxylases. Progress in lipid research. 2002;41(5):407–35.
W Z, Sb R-P, Z S, H Z. Improving cellular malonyl-CoA level in Escherichia coli via metabolic engineering. Metab Eng. 2009; 11(3):192–8.
Milke L, Kallscheuer N, Kappelmann J, Marienhagen J. Tailoring Corynebacterium glutamicum towards increased malonyl-CoA availability for efficient synthesis of the plant pentaketide noreugenin. Microbial Cell Factories. 2019;18(1):71.
An JH, Kim YS. A gene cluster encoding malonyl-CoA decarboxylase (MatA), malonyl-CoA synthetase (MatB) and a putative dicarboxylate carrier protein (MatC) in Rhizobium trifolii--cloning, sequencing, and expression of the enzymes in Escherichia coli. Eur J Biochem. 1998;257(2):395–402.
Wang Y, Chen H, Yu O. A plant malonyl-CoA synthetase enhances lipid content and polyketide yield in yeast cells. Appl Microbiol Biotechnol. 2014;98(12):5435–47.
Ferrer J-L, Jez JM, Bowman ME, Dixon RA, Noel JP. Structure of chalcone synthase and the molecular basis of plant polyketide biosynthesis. Nature Structural Biology. 1999;6(8):775–84.
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