Ketosis and Protein

I just wanted to throw out a few comments about the inhibition of ketogenesis by protein. The obvious effect, that of stimulating gluconeogenesis, appears to be at best a partial explanation of what happens.

I've long been interested in how amino acids feed into (and are derived from) the citric acid cycle and related pathways. Clearly any amino acid which metabolises to oxaloacetate within the liver is simply going to remove that void in the citric acid cycle (oxaloacetate deficiency) which results in acetyl-CoA being diverted to ketogenesis. Aspartate is one such. Those metabolising to pyruvate are also going to do essentially the same thing. There is no need for increased gluconeogenesis in this scenario. Gluconeogenesis may happen at a increased rate. It may not. Providing a source of oxaloacetate in the liver mitochondria will stop ketogenesis, whatever gluconeogenesis does, whatever insulin does.

Personally I am very ketoadapted. I've drifted in and out of ketosis since just after that start of the current century, probably around the summer of 2001 if I recall correctly. I find carbohydrate restriction effortless. Limiting to 30-40 grams per day is easy. Protein limitation is much more difficult. With about 20grams of protein in each breakfast and a few grams derived from cream, chocolate or macadamias at lunch time this does not leave a huge allowance for meat intake at suppertime. At around 65kg bodyweight nowadays keeping to 1g/kg is not the easiest target. A decent steak and I miss it. Life is too short to stress about this, but I certainly don't eat steak every day. Urinary ketones are always there at the + or ++ level. Exercise (distance walking) usually gives +++ as does the evening meal post prandial period, unless there have been excess chips with supper or I've gone significantly over my protein limit.

So I've limited protein, mildly, for years. My degree of keto adaptation still allows free generation of ketone bodies, certainly to a level where I can detect acetoacetate in my urine.

For some reason the concept of amino acids being derivatives of (and inputs towards) the TCA pulls me back to Nick Lane's ideas, the origin of life and the throwing together of metabolism. I'm willing to buy the reduction of CO2 by H2 to give formate as the starting point of metabolism. There is an energetic cost to this initial step but once going it's all down hill, energetically, to pyruvate. Many amino acids are formed from pyruvate and close derivatives. This makes sense. Evolution doesn't plan but does progress within the framework of what is available.

In modern biology DNA doesn't do very much other than replicate (I simplify). RNA is much more active, it carries the message out, assembles itself in to ribosomes and does all of the picking and choosing of amino acids etc to make a protein. I like to think of DNA as a rather stable "hard copy" of the information which was originally carried by the less stable RNA. As such DNA is the fossilisation of the amino acid preferences of primordial RNA. Written in to DNA are the remnants of what was probably a chemical associations of RNA with specific amino acids. If DNA specifies a cytosine at the start of a triplet then the amino acid chosen via transport RNA will be derived from alpha-ketoglutarate, if an adenine the coded amino acid will be oxaloacetate derived, if thymine it comes from pyruvate and if guanine the amino acid will be derived from any one of several possible small molecules. The second base specifies how hydrophobic/hydrophilic the chosen amino acid might be and these two cover a high proportion of the biological amino acids. The third base is degenerate, i.e. it doesn’t carry any specific information but does allow a wider pool of amino acids to be selected.

I'm afraid this is all rather cool to me.

I love these glimpses in to the early mish-mash of chemicals and how they might have interacted before life became seriously organised. What you can and cannot say about LUCA, the last universal common ancestor, and the first steps away from prebiotic chemistry, is largely determined by such biochemical fossils.

All of this random musing came from wondering whether amino acids might supply oxaloacetate and so suppress ketosis. Some do.

Well. Eating a steak is not very ketogenic. It’s hard to separate this from the origins of metabolism and of life, for me anyway,

Peter