The discovery of CH3CH(OH)CH2CO2H


CH3CH(OH)CH2CO2H = beta hydroxybutyrate. It’s a molecule your body makes from fats. The correct spelling is β-hydroxybutyrate or 3-hydroxybutyrate and is often abbreviated BHB. We’ll use beta hydroxybutyrate here.

It all started in 1887. Well, actually 22 years earlier in 1865 when scientists discovered a molecule called acetoacetate in the pee of diabetic patients. Acetoacetate is a ketone or also known as a ketone body. Discovering acetoacetate eventually led them to discover beta hydroxybutyrate. Beta hydroxybutyrate was found in high concentrations in uncontrolled diabetes and so was first thought of as bad.

That’s putting it mildly. Oliver Owen describes how “for years, researchers and scientists viewed ketone as monstrous materials signaling impending death (as in the case of diabetes mellitus)” . Good ol’ guilt by association, a notorious trap for the medical field. It’s like accusing firefighters of starting fires.Or accusing LDL cholesterol for causing heart disease . Only someone who doesn’t know what firefighters actually do would make that mistake.

Let’s start small and learn about the trees (beta hydroxybutyrate) to appreciate the forest (our body’s energy policies).

Beta hydroxybutyrate the impostor


Our liver cells (hepatocytes) have an assembly line other cells don’t have that turns fats and other molecular into a ketone called acetoacetateSome amount of acetoacetate then spontaneously turns into acetone without the help of fancy molecular machines (via non-enzymatic decarboxylation).On the other hand, one of these fancy enzymes called D-β-hydroxybutyrate dehydrogenase turns acetoacetate into beta hydroxybutyrate. This whole assembly line making ketones is called ketogenesis.

Ketogenesis gives us the Three Musketeers of the ketone world: acetoacetate (AcAc), acetone and beta hydroxybutyrate (BhB). The latter is an impostor, it’s not technically a ketone – but it’s counted as one.

Why do biologists call beta hydroxybutyrate a ketone when it’s a monocarboxylic acid? From what I can tell

  1. Chemistry is a weakness of many biologists (including me)
  2. Counting it as a ketone is an ossified convention by now
  3. The least worst reason is because they are functionally related to one another and originate from their shared ketogenesis pathway

For simplicity’s sake, let’s proceed with the understanding that beta hydroxybutyrate is one of the three ketone compadres. Rumour has it, it may have a dark side…

A two-faced impostor!

Everything should be made as simple as possible, but no simpler – Albert Einstein

When your body makes beta hydroxybutyrate (endogenous beta hydroxybutyrate) it comes in one version and when a lab makes it (exogenous beta hydroxybutyrate) it comes in another.

Do we metabolize endogenous versus exogenous beta hydroxybutyrate differently? If so, are those differences meaningful?

In answering that question let’s take care not to fall in the ‘appeal to nature’ trap, explained by Steven Pinker in the following way:

The naturalistic fallacy is the idea that what is found in nature is good”

We want to explore the advantages and disadvantages between exogenous and endogenous ketones because the ones our liver make are associated with mostly positive metabolic and physiological changes. Our skeletal muscle and in particular our heart happily gobbles up ketones when they’re around . Ketones can meet about 50% of your body’s energy needs .

So can we use exogenous ketones to tweak our biology and reap health or performance benefits?


Beta hydroxybutyrate’s good side: left or right?


Imagine two molecules having exactly the same chemical groups A, B and C in the same amounts. You can join them together in different ways: A=B=C, A=C=B, B=A=C, B=C=A and C=A=B. This is called structural isomerism (or constitutional isomerism).

The other kind of isomerism, spatial isomerism, still describes two molecules with exactly the same amount and type of chemical groups joined together in the same way (say A=B=C and A=B=C) but taking up different positions in space.

A kind of spatial isomer, enantiomers, are two molecules that are ‘the same’ except that one is ‘left-handed’ and the other ‘right-handed’. Literally like your hands! They’re identically structured except for being mirror images of each other. Since you were dying to know, all other spatial enantiomers that aren’t mirror images of one another are called diastereomers.

Your hands are enantiomers. D-β-hydroxybutyrate and L-β-hydroxybutyrate are enantiomers. Once your liver cells make beta hydroxybutyrate, specifically the right-handed version D-β-hydroxybutyrate, it can circulate around your body by dissolving in the water making up most of your blood. It can then cross over into your brain by passing through the blood-brain barrier and feed about two-thirds of your brain’s energy needs together with acetoacetate when required .

Our bodies make D-β-hydroxybutyrate, the right-handed version. “D” comes from the latin dexter. Lab-made ketones are currently made as L-β-hydroxybutyrate, the left-handed version. “L” comes from the Latin laevus.

So where’s the controversy?


The primary controversy boils down to disagreements over the safety of the left-handed versus right-handed forms of lab-made ketone supplements. Some argue only the endogenously produced right-hand form is safe for us, others argue a mixture of both is handled just fine if not better.

Making a right-handed only beta hydroxybutyrate supplement is expensive. One ketone supplement of this type is a di-ester alcohol called (R)-3-hydroxybutyl (R)-3-hydroxybutyrateThe di-ester first gets broken down to D-β-hydroxybutyrate and 1,3-Butanediol, and 1,3-Butanediol then becomes D-β-hydroxybutyrate too. This di-ester ends up as the right-handed form of beta hydroxybutyrate only.

Making a ketone supplement with both the left and right-handed version of beta hydroxybutyrate is much less expensive. One kind of ketone supplement that is a mixture of the left and right-handed beta hydroxybutyrate is technically known as a racemic mixture of ketone saltsThese ketone salts are left or right-handed beta hydroxybutyrate molecules linked to a mineral, such sodium (Na), calcium (Ca) or potassium (K) for example. This kind of ketone supplement gets broken down to left and right-handed version of beta hydroxybutyrate and the mineral in question.

Left vs Right controversy


It has been argued that the right-handed version of beta hydroxybutyrate produced by our bodies and some labs are more energetically efficient than racemic mixtures. And that it also recharges internally generated antioxidant stores beyond that which left-handed beta hydroxybutyrate can. Another argument against against taking a mix of left and right-handed ketones is that if your were to measure your blood ketones with a device like the Precision Xtra that only recognize the right-handed (D) form, the left-handed (L) form in your blood would be ignored, potentially leading to a dangerous underestimate. These arguments are made by brilliant ground-breaking researchers like Dr.Veech .

Dr.D’Agostino disagree with Dr.Veech, saying “across the board everything is positive there’s no negative thing” . He also explains that 24 to 48hrs after ingesting a racemic mixture of ketone salts, about 80% turn to the right-handed form and the remaining 20% of left-handed beta hydroxybutyrate gets metabolized for energy just like fats do. Most importantly, Dr.D’Agostino points out that racemic mixtures of ketones have been used since the late 1950s, amounting to millions of doses taken by humans nowadays with no evidence of harm. He also reminds skeptics that so far, racemic ketone supplements have been shown to lower oxidative stress, protect animals against hypoxia, stroke, brain injury and protect humans against various disorders like MAD and glycogen storage disease – just to name a few applications.

Are exogenous ketones safe?


So far they seem to be. There’s mounting evidence that they can help treat more and more conditions. Furthermore, the continued absence of evidence of adverse events is encouraging.

Some remaining questions

  • We talked about racemic ketone salts, but what about racemic ketone esters? What are the respective advantages and disadvantages?
  • What are the effects of having high amounts of sodium, calcium or potassium that necessarily accompany the ingestion of ketone salts?
  • Ketone supplements can enhance insulin sensitivity for glucose utilization (a “good thing”) yet ketone supplements acutely spike insulin and stop the release of fats from fat cells (a “bad thing”) – how do we reconcile these phenomena?
  • What about ketone supplements combining beta hydroxybutyrate and another ketone, namely acetoacetate? Is the combination better, the same or worse?

Lets continue the discussion in the Q&A forum


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