José L. Avalos
Research AreaBiochemistry, Biophysics & Structural Biology
Research FocusMetabolic engineering, organelle engineering, synthetic biology, structural biology, and protein engineering
Metabolic engineering is the application of genetic engineering to modify and optimize the metabolism and regulatory systems of an organism to produce or degrade a desired compound. We are currently focused on engineering microorganisms (mostly yeasts) for two possible goals: 1) to produce molecules of commercial value, such as biofuels, bioplastics, commodity chemicals, or specialty chemicals (drugs, pigments, flavorants, etc.) from renewable sources, including cellulosic biomass; or 2) to degrade or remove contaminants from the environment (bioremediation).
Subcellular engineering is a fast-growing field in bioengineering, in which metabolic pathways or other synthetic functions are targeted to specific cellular organelles to take advantage of their unique environments, metabolites, and enzymes, as well as their physical separation from the cytosol. We are particularly interested in mitochondrial engineering, where we have shown that targeting metabolic pathways to yeast mitochondria is an effective way to enhance the productivity of engineered pathways. In addition, we are interested in engineering the mitochondrial physiology to enhance metabolic pathways targeted to this highly dynamic, and versatile organelle.
Synthetic biology combines molecular biology, genetic engineering (including genome editing), directed evolution, biophysics, computational biology, and protein engineering, aiming to generate synthetic phenotypes (analogous to synthetic chemistry aiming to generate synthetic molecules by designing series of chemical reactions). We are particularly interested in developing biosensors and regulatory genetic circuits applicable to metabolic engineering. Biosensors are useful to measure, monitor, screen, or select for desired functions (either natural or engineered). Genetic circuits are useful to control engineered metabolisms and other engineered functions in the cell.
Structural Biology and Protein Engineering
Our efforts in synthetic biology and metabolic engineering are complemented by fundamental studies on the molecular structure and function of the proteins involved, such as enzymes, transmembrane transporters, receptors, and transcription factors. To study these proteins in molecular detail, we use different biophysical and biochemical methods, including X-ray crystallography. Understanding the relationship between the structure and function of these proteins significantly enhances our ability to engineer them with new functions relevant to metabolic engineering or synthetic biology.
Optogenetic regulation of engineered cellular metabolism for microbial chemical production. Nature. 2018 ;555(7698):683-687. .
Current and future modalities of dynamic control in metabolic engineering. Curr Opin Biotechnol. 2018 ;52:56-65. .
Uncovering the role of branched-chain amino acid transaminases in Saccharomyces cerevisiae isobutanol biosynthesis. Metab Eng. 2017 ;44:302-312. .
Harnessing yeast organelles for metabolic engineering. Nat Chem Biol. 2017 ;13(8):823-832. .
Traditional and novel tools to probe the mitochondrial metabolism in health and disease. Wiley Interdiscip Rev Syst Biol Med. 2017 ;9(2). .
Metabolic engineering: Biosensors get the green light. Nat Chem Biol. 2016 ;12(11):894-895. .
Compartmentalization of metabolic pathways in yeast mitochondria improves the production of branched-chain alcohols. Nat Biotechnol. 2013 ;31(4):335-41. .
Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution. Science. 2009 ;326(5960):1668-74. .
The structural basis of sirtuin substrate affinity. Biochemistry. 2006 ;45(24):7511-21. .
Insights into the sirtuin mechanism from ternary complexes containing NAD+ and acetylated peptide. Structure. 2006 ;14(8):1231-40. .
Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell. 2005 ;17(6):855-68. .