An Interesting Cluster Relating to Proline Metabolism: a Risky Conjecture



Here is an interesting cluster that clearly has something to do with proline metabolism. Here are two KEGG maps, Arginine and proline metabolism and Ascorbate and aldarate metabolism.

I have tried to highlight the enzymes in question:

  1. 4-hydroxyproline epimerase (EC 5.1.1.8) shown as the blue genes numbered 3,
  2. D-amino-acid oxidase (EC 1.4.3.3) the green genes numbered 2,
  3. 1-pyrroline-4-hydroxy-2-carboxylate deaminase (EC 3.5.4.22) shown as the purple genes numbered 4,
  4. the red gene numbered 1.


The conjecture that I would like people to consider is that the red genes are really 2,5-dioxopentanoate:NADP+ 5-oxidoreductaseZ, which takes 2,5-dioxopentanoate to 2-oxoglutarate.

I am not prepared to adequately defend this hypothesis. There are numerous uncertainties in some of the other annotations. However, I do advance the conjecture for others to consider.
Response from Sveta:

Ross,

This oxidoreductase does indeed seem to cluster with this novel pathway of 4-hydroxyproline - you are right! But I don't think it is "2,5-dioxopentanoate:NADP+ 5-oxidoreductase, EC 1.2.1.26", as you suggest. Because:

(i) this function is already assigned in the cluster you show - it is number 5 in your display, but annotated with a synonym (note the same EC number):

"Ketoglutarate semialdehyde dehydrogenase (EC 1.2.1.26) # hydroxy-L-proline-inducible"

(2) It is one of a few enzymes in this largely predicted pathway that has been actually studied experimentally - so the existing assignments for 1.2.1.26 are rather reliable. Pls see ref below.

But how did you arrive at this prediction?! It could have been true easily (if there wouldn't have been another candidate nearby already). I hope, I understood you correctly. Please, let me know if I am wrong. I don't dare predicting any specific function for it, since the pathway is so poorly understood still... But it needs to be included in this SS - you are right. I did. Thank you for suggestion! I have uploaded an updated version of this SS from Annot SEED to UChicago SEED s

Watanabe S., M.Yamada|, Ohtsu I., and Makino K. 2007. Alpha-Ketoglutaric Semialdehyde Dehydrogenase Isozymes Involved in Metabolic Pathways of D-Glucarate, D-Galactarate, and Hydroxy-L-proline. Molecular and Metabolic Convergent Evolution. J. Biol. Chem., 282(9):6685-6695

I then added the following comment:

I have carefully reconsidered the situation for 13 seconds, and it is now apparent to me that the oxioreductase in question is really

L-Proline,2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating) (EC 1.14.11.2)

Doesn't that fit nicely?