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Promiscuity, serendipity, and metabolic innovation

Award Number: R01GM135364
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Promiscuity, serendipity, and metabolic innovation - Bioinformatic and structure/function studies suggest that most extant metabolic pathways were patched together from previously existing promiscuous enzyme activities that, even if inefficient, provided some degree of catalysis. However, we cannot explain why certain pathways arose rather than the thousands of other possibilities. Further, we have little insight into the process by which novel pathways were patched together and flux was improved via mutations. This project will exploit a model system in which the pathway for synthesis of pyridoxal 5- phosphate (PLP) has been disrupted to identify “serendipitous pathways” (SPs) that restore PLP synthesis by patching together promiscuous activities of enzymes that normally serve other functions. The enzymes that catalyze steps in SPs will be characterized. The mechanisms by which mutations increase flux through a SP to a physiologically significant level will be identified. Finally, the dependence of the evolutionary outcome on environmental conditions and genome content will be defined. The feasibility of this project is supported by preliminary results identifying two SPs after evolution of ∆pdxB E. coli in different conditions and evidence that PLP synthesis can be restored after evolution in other conditions, as well. Biochemical, genetic, and metabolomics approaches have revealed the mechanisms by which mutations enabled assembly of one of these SPs. E. coli and other bacteria in which a gene required for PLP synthesis has been deleted will be subjected to laboratory evolution. If growth can be restored, the responsible mutations will be identified. The mechanisms by which these mutations have facilitated recruitment of a promiscuous enzyme to replace the missing enzyme, or, more interestingly, emergence of a SP will be defined using a battery of biochemical, genetic and ‘omics approaches. This project will provide new insights into the assembly of metabolic pathways, how genome content and growth conditions affect the evolution of novel pathways, and how flux through initially inefficient pathways can be elevated due to mutations. These insights will help us understand how bacteria have evolved throughout the history of life on earth, and how they will continue to evolve as humans exert new selective pressures due to introduction of anthropogenic chemicals such as pesticides and pharmaceuticals. Evolution of pathways capable for degradation of anthropogenic compounds is critical to minimize adverse effects on the health of ecosystems and humans. On the other hand, evolution of novel pathways might be an unrecognized mechanism for resistance to antimetabolite drugs used to treat infectious diseases and cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	4	3/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $335,675 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	4	5/2/2023	NON-COMPETING CONTINUATION	$335,675
														Subtotal = $335,675

Issue Date FY: 2022 ( Subtotal = $372,935 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	3	6/16/2022	NON-COMPETING CONTINUATION	$37,296
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	3	2/11/2022	NON-COMPETING CONTINUATION	$335,639
														Subtotal = $372,935

Issue Date FY: 2021 ( Subtotal = $344,120 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	2	2/17/2021	NON-COMPETING CONTINUATION	$344,120
														Subtotal = $344,120

Issue Date FY: 2020 ( Subtotal = $337,279 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	1	4/10/2020	NEW	$337,279
														Subtotal = $337,279

Grand Total All Awards = $1,390,009

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Promiscuity, serendipity, and metabolic innovation

Award Number: R01GM135364

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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