My understanding is that he’s a specialist. Foggy only. Like a left handed reliever

This is why I write a little bit of magical thinking into all abstracts.

I have been saying this. It’s an abomination. The only thing that comes close is the Quizno’s spongmonkeys.

19/Work from the Yang group: www.jci.org/articles/vie...

18/Work from the Jourdain group: www.biorxiv.org/content/10.1...

17/NUDT5 is having a moment – see excellent work from other labs reporting roles for NUDT5 in purine metabolism. These include papers by Kilian Huber and Stefan Kubicek, also out today (see link), and work by Alexis Jourdain and Jun Yang (see next posts)
www.science.org/doi/10.1126/...

16/TL/DR: The DNPB pathway has been known since the 1950s, and thiopurines have been used almost as long. NUDT5 regulates the activity of this pathway, and sensitivity to drugs that block it.

15/A fascinating open question is exactly what induces the association between NUDT5 and PPAT, and whether/how this triggers disassembly of the purinosome.

14/When purines are abundant, the purinosome disassembles, but this requires NUDT5-PPAT binding. So NUDT5 controls both the biochemistry and cell biology of DNPB initiation.

13/Also interesting: DNPB involves a cytosolic complex called the purinosome, which colocalizes the DNPB enzymes together to channel metabolites along the pathway. NUDT5 regulates the purisonome through the same residues that bind PPAT.

12/Interestingly, NUDT5’s ability to suppress DNPB explains how it confers 6TG sensitivity. 6TG induces the same DNA damage in wild-type and NUDT5-deficient cells, but only the latter cells survive. Blocking residual DNPB kills NUDT5-deficient cells treated with 6TG.

11/The NUDT5-PPAT complex seems to hold PPAT into an inactive oligomer (likely a tetramer) that suppresses DNPB. In vitro, NUDT5 reduces PPAT enzymatic activity, much better than purine nucleotides alone. But this requires that NUDT5 associate with PPAT.

10/Mutating a single NUDT5 residue from the interface with PPAT eliminated NUDT5’s ability to bind PPAT and confer sensitivity to 6TG, both in cultured cells and xenografted tumors.

9/Zheng found that NUDT5’s catalytic activity is dispensable for its ability to confer sensitivity to 6TG. Rather, he found through interactome databases and computational analysis of coevolutionary signals that NUDT5 physically associates with PPAT.

8/NUDT5’s involvement was surprising. R5P provides the pentose for purines, but Zheng had shown that mitochondrial suppression massively increases R5P abundance by activating the pentose phosphate pathway. He thought NUDT5 might have a different role.

7/The screen identified HPRT1, the salvage enzyme that converts 6TG into toxic thiopurine nucleotides. That made sense. It also identified NUDT5, a hydrolase that cleaves ADP-ribose to produce ribose-5-phosphate (R5P).

6/Thiopurines are salvaged to produce thiopurine nucleotides, which inhibit DNPB and incorporate into DNA, resulting in DNA damage and cell death. So a screen for suppressors of 6TG toxicity could identify genes required to activate salvage or suppress DNPB.