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Ketogenesis pathway maps show acetoacetyl-CoA converted to HMG-CoA and only then to the first ketone body acetoacetate. Why this detour instead of directly hydrolyzing off the CoA to get there in a single step? Is it possible that some ketone bodies are made by direct conversion? The enzyme acetoacetyl-CoA hydrolase to do this job exists and can be found in rats.

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    $\begingroup$ I've been Googling this a bit and the trail seems to run dry for the acetoacetylCoA hydrolase after about 1980. I suspect that there is something fishy about it. I notice that the acetyCoA hydrolase turned out to be an alternative activity of the thiolase, and wonder if it is something similar and is not active under the appropriate physiological conditions. There aren’t many biochemists around these days that know about this stuff, and I don’t rate your chances of finding one on this list, but I hope I am proved wrong. Fair question, though. $\endgroup$ – David May 14 '18 at 21:57
  • $\begingroup$ Thanks David for researching this. Too bad we both came up short so far. A future research project hopefully. $\endgroup$ – SeanJ May 18 '18 at 7:21
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I believe it is related to the fact that the enzyme HMG-CoA lyase is regulated by glucagon (activates) and insulin (inactivates). It appears that this extra step was added so the pathway can be hormonally regulated.

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  • $\begingroup$ Welcome to Biology.SE! I could see this as a mechanism for maintaining a step, but I don't see how adding an extra step to an existing pathway could be selected for especially to allow future regulation. In addition, answers are much more likely to receive a favorable response if you include supporting references (primary literature is best). Without that support, your answer is indistinguishable from opinion. ——— You may also want to take the tour and then consult the help pages for additional advice on How to Answer effectively on this site and edit your answer accordingly. Thank you! 😊 $\endgroup$ – tyersome Feb 26 at 21:18
  • $\begingroup$ This is a good example of how to format references. $\endgroup$ – tyersome Feb 26 at 21:19
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After further checking, I found that HMG-CoA synthase rather than HMG-CoA lyase is the enzyme which is regulated. This enzyme also plays a vital role in cholesterol synthesis. HMG so produced can either form mevalonate, which leads to cholesterol synthesis, or form acetoacetate. Therefore if acetoacetyl CoA were directly hydrolyzed, it would short circuit the cholesterol pathway.

The enzyme can be regulated by succinylation. Its synthesis can be regulated by several transcription factors. Evidence suggests that hormones play a role in each of these processes. References: Harris, et al., Journal of Investigative Dermatology 114(1) 83-87 (2001); F.G. Haggart, Biochem. J. Mar. 5, 338 (pt. 3) 569-582 (1999); Quant, P.A. et al. Eur. J. Biochem. 187, 169-174 (1987)

Most Biochemistry texts today list HMG-CoA as the source of acetoacetate with no mention of direct hydrolysis of acetoacetyl-CoA. This suggests that if direct hydrolysis of acetoacetyl-CoA does occur, it probably plays a very minor role.

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    $\begingroup$ If you wish to post a second answer to a question it should stand alone and not refer to a first one you have (or should have) reservations about. You are able to edit or delete any answer you post, so I would suggest you do this to consolidate them into a single answer, comprehensible in itself. (And as one of the few people who answer questions on biochemical metabolism I’ll have a look at it when I have a moment.) $\endgroup$ – David Feb 28 at 22:50
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    $\begingroup$ Since you now seem to be posting using two separate accounts, you may find this information on merging accounts to be of interest ... $\endgroup$ – tyersome Feb 29 at 19:51

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