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Himanshu Dhamankar

Graduate Student

Department of Chemical Engineering
Massachusetts Institute of Technology
Room: E18-524
77 Massachusetts Ave.
Cambridge, MA 02139 USA

Phone: (617) 258-8037
E-mail: himanshu@mit.edu

Education

M.S. Chemical Engineering Practice
Massachusetts Institute of Technology 2009

Bachelor of Chemical Engineering
Institute of Chemical Technology, Mumbai, India 2007

Research Description

Microbial synthesis of 3-hydroxyalkanoic acids:

Our society today is heavily dependent on fossil reserves and crude petroleum to provide us with fuels and an array of value-added petrochemicals that find applications in our day to day lives.  Reducing our dependence on these dwindling non-renewable resources requires us to figure out ways to convert biomass (as a renewable resource) not only into biofuels but also value-added biochemicals to serve as replacements for petrochemicals and to effectively complement biofuels in a biorefinery.  A major limitation in converting biomass into specific desired products is the availability of conversion technologies.  In the Prather Lab we address this challenge using an approach called ‘De novo pathway engineering’- the construction of novel pathways for the microbial synthesis of value-added products, combining partial natural pathways and exploiting naturally evolved enzymes and their promiscuity to catalyze reactions with non-natural substrates that allows us to expand the repertoire of microbially synthesized products beyond natural products (Dhamankar and Prather, 2011).  We are particularly interested in constructing pathways in E. coli for molecules with no known natural biosynthetic routes.

My work focuses on using this approach to design and engineer a novel pathway for the synthesis of 3-hydroxyalkanoic acids (3HA) as value-added chemicals that can serve as monomers for biodegradable polymers (polyhydroxyalkanoates (PHAs)) and building blocks for chiral pharmaceuticals and chemicals.  We have established a platform pathway in E. coli that allows stereospecific synthesis of novel straight and branched chain 3HAs using glucose and small acid molecules as staring materials. By feeding different small acid molecules to E. coli cells expressing the pathway enzymes, different 3-hydroxyalkanoic acids (the carbon chain length and substituents in which depend on the supplied small acid molecule) may be synthesized.  Using this pathway we have been successful in establishing the first biosynthetic route towards the valuable pharmaceutical building block 3-hydroxybutyrolactone (3-HBL) and 3,4-dihydroxybutyric acid (the free acid form of 3-HBL) from glycolic acid as a small acid molecule and have demonstrated synthesis of 3-HBL from glucose as a sole carbon source, achieving up to 27% of the maximum theoretical yield.  3-HBL can serve as a building block for a variety of blockbuster pharmaceutical drugs including the synthetic statin drugs Crestor® and Lipitor®, the antibiotic Zyvox® and the anti-hyperlipidemic Zetia® and the nutritional supplement L-carnitine and features on the DOE’s 2004 list of ‘Top Value-Added Chemicals from Biomass’ (Werpy and Peterson, 2004).  3-HBL is currently synthesized using chemical synthesis routes that suffer from various disadvantages (including poor selectivity and yield, high cost of synthesis and harsh and hazardous processing conditions).  A fermentation process based on our biosynthetic route is expected to alleviate these issues and allow economical synthesis of this valuable product. We have also demonstrated synthesis of novel PHA monomers 3-hydroxyhexanoic acid and 4-methyl-3-hydroxyvaleric acid from butyric acid and isobutyric acid respectively. PHAs are environmentally friendly biodegradable polymers the chemical and physical properties of which depend on the constituent monomer.  The synthesis of new monomers is thus important from the point of view of enhancing the range of properties of these novel materials.

We are now directing further efforts to enhance the productivity of the pathway by a) identifying additional alternative pathway enzymes (homologous to our already identified enzymes) with higher selectivity and activity b) enhancing selectivity / activity via protein engineering and c) metabolic engineering of cells by eliminating competing pathways that consume pathway intermediates and reduce yield.  We are also looking at extending the pathway towards additional value-added products by testing out various substrates as also protein engineering to improve the versatility of the pathway.  The ultimate goal is to improve the yields and pathway productivity sufficiently at the lab scale (in particular for 3-HBL but also for a variety of different products) to allow successful commercialization of these products as biomass derived renewable alternatives to conventional petrochemicals.

References:


Dhamankar, H and K. L. J. Prather. 2011. “Microbial chemical factories: recent advances in pathway engineering for synthesis of value added chemicals.” Curr. Opin. Struct. Biol. 21(4):488-494. doi: 10.1016/j.sbi.2011.05.001

Werpy T. and Peterson G. 2004. “Top Value Added Chemicals from Biomass Volume I”. http://www1.eere.energy.gov/biomass/pdfs/35523.pdf

Publications

Dhamankar, H and K. L. J. Prather. 2011. “Microbial chemical factories: recent advances in pathway engineering for synthesis of value added chemicals.” Curr. Opin. Struct. Biol. 21(4):488-494. doi: 10.1016/j.sbi.2011.05.001

Sholten, E., Dhamankar, H., Bromberg, L., Rutledge, G.C. and Hatton, T.A. 2011. “ Electrospray as a tool for drug micro- and nanoparticle patterning”, Langmuir 27(11):6683-6688. doi:  10.1021/la201065n