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Normally fatty acids in the form of acyl CoA are converted to acyl carnitine in a reaction catalysed by carnitine palmitoyltransferase I (CPT1), which is also known as carnitine acyltransferase I. This allows them to be transported across the inner mitochondrial membrane by a translocase when the acyl CoA is regenerated in a reaction that is chemically identical but catalysed by a different enzyme, carnitine palmitoyltransferase II (CPT2).

As a result of observations I have made (detailed below) I wish to known whether acyl carnitine that has not entered into the mitochondria — either present in the cytosol or blood/plasma — can be converted back into acyl CoA without entering mitochondria?

Essentially, does a reaction like that catalysed by CPT2 occur outside of the inner-mitochondrial matrix?

Elaboration

I'm studying plasma metabolites. During fasting there is an increase in plasma acylcarnitines due to increased fat utilization/beta oxidation. If the fast is broken, acylcarnitines are typically supposed to drop. Oddly, some people experience an increase in plasma acylcarnitines 0-30 minutes following eating - but then they drop after the 30 minutes. I'm confused as 30 minutes after food ingestion, elevated circulating insulin levels are still present and should be still working to inhibit the majority of fatty acid oxidation - yet the odd increase and then drop in acylcarnitines after 30 minutes of food intake still exists.

So it leaves me with the question, is there another pathway in which acylcarnitines are converted back to acyl CoA outside of the mitochondria? In short, how does the cell recall fatty acids that are destined for the mitochondria?

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  • $\begingroup$ This is a rather precise question in a specialized biochemical area, but seems rather strange to me. Is there a reason for asking? If you can explain a little further it is more likely that someone will be able to help you. At the moment all I can do is summarize what I can glean from standard biochemistry texts. $\endgroup$ – David Jan 15 '18 at 23:08
  • $\begingroup$ @David I updated the question to reflect your comment. I understand this is a harder question, not a lot research out there on it, but I was hoping to throw this out there to see if anyone has heard anything or can point me in a direction to research further. Regarding the strangeness of the questions, it is basically introductory metabolism (beta-oxidation) with a twist. $\endgroup$ – Aaron43 Jan 16 '18 at 12:11
  • $\begingroup$ Your clarification was helpful, and after a first go at an answer I have modified your question to provide the background biochemistry for anyone not familiar with it. $\endgroup$ – David Jan 16 '18 at 21:07
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  1. The introduction to Ann N Y Acad Sci. (2004) 1033:17–29 lists the various carnitine acyltransferases and mentions CPT-1a, CPT-1b, CPT-1c (tissue specific) but states there is only a single CPT-2 in humans. It does not appear that there is any other variant, so extra-mitochondrial conversion of acyl carnitine to acyl CoA would require a post-translational variant of CPT-2, or CPT-1 working in the reverse direction.

  2. The discussion of carnitine metabolism in Berg et al., Section 22, implies the reaction is near equilibrium. Hence, if the concentrations of substrate and product were appropriate it would be thermodynamically possible for CPT-1 to operate in the reverse direction.

  3. Thermodynamically possible does not necessarily mean enzymically possible. I am not familiar with kinetic studies on CPT-1 and CPT-2, but imagine that CPT-1 has a higher affinity for acyl CoA and carnitine than for the product acyl carnitine, and that the reverse situation holds for CPT-2. I imagine that the ability of CPT-1 (or one particular isoform) to catalyse the reverse reaction in physiological circumstances would depend on its Km for acyl carnitine and the concentration of the latter. It might be worth seeing what kinetic analysis has been done.

  4. The ‘appropriate’ situation for (2) might be if something were preventing utilization of acyl carnitine in the mitochondria of ‘target’ cells.

  5. If you work in this area you will know better than me that there are various clinical conditions and sub-clinical conditions (e.g. obesity) that result in abnormal utilization of acyl carnitine. Could the abnormal instances you observe be for such individuals?

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  • $\begingroup$ I don't claim that this is a complete answer, but it tries to address the question in terms of possibilities. It has been modified since I originally wrote it. $\endgroup$ – David Jan 16 '18 at 21:13
  • $\begingroup$ Awesome, thanks for editing the question, and providing a more than substantial answer. Personally, I was thinking that there could be affinity exchanges, perhaps a short-chain acyl-coa might be a preferred substrate of CPT1, and thus might remove carnitines (somehow) from long-chain fatty acids in favor of switching the carnitine group onto a short-chain acyl-coa. That is just a completely unresearched guess though. I do work in the field of metabolomics, but surprisingly this is an unanswered question. But anyway, thanks again for the informative response. $\endgroup$ – Aaron43 Jan 17 '18 at 15:52
  • $\begingroup$ @Aaron43 — Glad you found my remarks of use. I appreciate the difficulty of interpreting metabolomics data. One problem is that classical biochemical metabolic research went out of fashion because it seemed more or less finished and there were newer and more exciting fields that deserved research funds. However now that the old guys are gone there's a serious shortage of people who understand metabolism to interpret all the new omics stuff. I looked down on it too, but was obliged to teach it in the later stages of my career. Discovered that there are lots of interesting questions left. $\endgroup$ – David Jan 17 '18 at 19:11
  • $\begingroup$ lol, the complexity and the almost infinite number of metabolic interpretations that can come from something as simple as plasma metabolite concentrations, really makes the field seem like chaos. Even my own work I have to step back sometimes and just say wtf. Ha, but thanks again for the info. $\endgroup$ – Aaron43 Jan 19 '18 at 17:30

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