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Biology subjects

Scott, D. C.

Publications and source records attributed to Scott, D. C..

2 recordsLinked to original sources

Metabolic blueprints of monocultures enable prediction and design of synthetic microbial consortia

Synthetic microbial ecology aims at designing communities with desired properties based on mathematical models of individual organisms. It is unclear whether simplified models harbor enough detail to predict the composition of synthetic communities in metabolically complex environments. Here, we use longitudinal exometabolite data of monocultures for 15 rhizosphere bacteria to parametrize a consumer-resource model, which we use to predict pairwise co-cultures and higher order communities. The capacity to artificially "switch off" cross-feeding interactions in the model demonstrates their importance in ecosystem structure. Leave-one-out and leave-two-out experiments demonstrate that pairwise co-cultures do not necessarily capture inter-species interactions within larger communities and broadly highlight the nonlinearity of interactions. Finally, we demonstrate that our model can be used to identify new sub-communities of three strains with high likelihood of coexistence. Our results establish hybrid mechanistic and data-driven metabolic models as a promising and extendable framework for predicting and engineering microbial communities.

systems biology↗

Monovalent Pseudo-Natural Product Degraders Supercharge the Native Degradation of IDO1 by KLHDC3

Targeted protein degradation (TPD) modulates protein function beyond inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating proximity between a neosubstrate and hijacked E3 ligase. Here, we identified pseudo-natural products derived from (-)-myrtanol, termed iDegs that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2KLHDC3, which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce formation of kynurenine by both inhibition and induced degradation of the enzyme and, thus, would also modulate non-enzymatic functions of IDO1. This unique mechanism of action may open up new therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.

cell biology↗