Molecular biology on Pluribus. Rate their cloning protocol.

Lastly, we wanted to determine how dysfunctional 4-HA catabolism affects physiology and generated ACAD11 KO mice. Disruption of ACAD11 in vivo leads to accumulation in plasma 4-HAs, higher susceptibility to diet-induced fat gain, and dysfunctional adipogenesis. 🧐

If they have similar activities, are ACAD10/11 redundant in cells? Our metabolomics results suggest they are not! ACAD10 is in mitochondrial and ACAD11 is peroxisomal, and we propose that their differential localization enables cells to catabolize a wider range of 4-hydroxy acids.

Second, 4-phosphoacyl-CoA serves as a substrate for the ACAD domains, which convert it into 2-enoyl-CoA using a “redox-neutral” FAD-dependent mechanism. ACAD10/11 are unable to oxidize saturated acyl-CoAs and use a specialized motif to recognize 4-phosphoacyl-CoA.🤯🤯

How do they pull off the job? First, they use N-terminal kinase domains that specifically recognize and phosphorylate 4-hydroxyacyl-CoA. This phosphorylation is crucial for priming the elimination of the “FAO-incompatible” 4-hydroxyl group.

Using rigorous biochemistry/cryo-EM, we demonstrate that ACAD10/11 convert 4-hydroxyacyl-CoAs into 2-enoyl-CoA intermediates that can enter the FAO pathway. They both conduct a multi-step reaction that centers around a key (and 🧊very cool🧊) PHOSPHORYLATED acyl-CoA intermediate.

Motivated to understand the biology of 4-hydroxy acids (4-HAs) in mammals, we sought to discover and study the enzymes responsible for their metabolism. It was a 3AM bacterial homology analysis that led us to think of ACAD10 and ACAD11 as likely candidates for this pathway (see Figure 1)

Fatty acid B-oxidation (FAO) is the primary pathway by which fatty acids are catabolized. However, some fatty acids are modified and need to be fixed to become “FAO-compatible”. One such class is 4-hydroxy acids, which are present in diet and living systems including humans.

We out here!! #StandUpForScience #Boston

Vermont ice fishing trip with @mvhlab.bsky.social was a success!! Everyone caught something. Congrats to Matt on his pike.

It's ice fishing season, kids.

A delightful surprise during my experiment!

Absolutely love this Bodega cat puzzle.

The second spread is complete!!

The spread is complete!!