Synthesis of β-Hydroxybutyrate
As described in the Ketone Body Reduction of Oxidative Stress pathway, an important product that arises from intermittent fasting is β-hydroxybutyrate. This ketone body is synthesized in the liver during fasted conditions that require the breakdown of fat tissue into 2-carbon Acetyl CoA units. β-hydroxybutyrate is essential for fighting oxidative stress – through direct reaction with reactive oxygen species (ROS), promotion of anti-oxidant gene transcription, and more [17]. In this section, we will dive into the chemical mechanism of the formation of β-hydroxybutyrate by several enzymes, as well as a brief note on how this molecule can interact with ROS.
Note: Any general basic amino acid residues present in various active sites that play a role in the catalysis are denoted as “B⁻”, as well as general acid catalysts denoted as “H-B”.
The first enzyme required in this pathway is thiolase, which catalyzes the condensation of two acetyl CoA molecules into a molecule acetoacetyl-CoA. The mechanism for this reaction uses two cysteine residues and one histidine residue for the catalysis (Figure 1).
The next step in the formation of β-hydroxybutyrate is β-hydroxy-β-methylglutaryl-CoA Synthase, also known as HMG-CoA Synthase. The mechanism for this reaction is shown below (Figure 2):
The formation of β-hydroxy-β-methylglutaryl-CoA is followed by a cleavage reaction, catalyzed by β-hydroxy-β-methylglutaryl-CoA Lyase (HMG-CoA Lyase). The mechanism for this reaction is shown below (Figure 3):
HMG-CoA Lyase catalyzes the formation of acetoacetate, which can reversibly be reduced into β-hydroxybutyrate via β-hydroxybutyrate Dehydrogenase. With a proton and a molecule of NADH, the conversion of two acetyl CoA molecules into β-hydroxybutyrate is complete (Figure 4).
Anti-oxidant Action of β-Hydroxybutyrate
β-hydroxybutyrate is an important ketone body known to suppress ROS and combat oxidative stress in the body through both direct and indirect mechanisms. This metabolite can directly interact with free oxygen radicals in mitochondria and other parts of cells. It also plays a role in histone acetylation, which impacts the transcription of several antioxidant defense genes [17].
Once again, nice work on this stuff. I noticed in the figure 1 caption that Acetoacetyl-CoA is spelled incorrectly. I also think it might be worth it to include the proposed free radical reaction in this section here while it is briefly mentioned, referring to another section for more information. Briefly scanning through the other sections, I wasn’t able to find this mentioned mechanism, but there is a chance that I simply missed it on one of the pages. Otherwise the mechanisms and information here all looks great to me.
Thank you Ryan! I fixed the spelling mistake in figure 1. Unfortunately, I had a lot of trouble finding the free radical mechanism and decided to focus on the synthesis pathway to make the ketone bodies instead. I do agree that the free radical mechanism would be helpful and beneficial, but I was unable to find it.
What really makes this page so great is the choice of color coding each important molecule within the mechanism. This makes it really easy to follow how each molecule is being incorporated to form the final product. For example, in formation of β-hydroxybutyrate via HMG-CoA synthase, I can easily trace the source of each molecule, clearly see how the previously synthesized acetoacetyl-CoA (Pink + Blue) is being introduced into the enzyme active site and being used to form the next product. The quick overview of β-hydroxybutyrate’s role in reducing oxidative stress also served as a helpful reminder of its significance, an idea that was previously explored in the Ketone Body Reduction of Oxidative Stress page.
This mechanism was very easy to follow, and I really liked how you denoted each section of carbons in any given structure by their colors, as Pun mentioned. It made backtracking very simple to do. One aspect that I would edit is in your last paragraph, when describing the antioxidant action of beta-hydroxybutyrate. You mention that this molecule impacts the “transcription of several antioxidant defense genes” in the first paragraph as well. Perhaps you could elaborate on a select few of these genes and their distinct advantages? Doing so can help mitigate redundancy since in one part you can go into the specifics while in the other part you can simply quickly identify those genes to sum everything up.
Nice page. In Figure 1, it appears that the histidine is missing a bond connecting it to the enzyme. I really liked how the acetyl-CoA groups are labeled, but a different color for the third acetyl-CoA would be nice; it’s hard to see. More background on the lack of specific residues for β-hydroxy-β-methylglutaryl-CoA Synthase and HMG-CoA Lyase would be nice. I also liked the explanations given for each enzyme to supplement what is shown in the figures.
Figure 1 is fixed.
Similar to other pages, the flow of information is great. The mechanism can be clearly followed with frequent description of what is happening. As already stated by one group member, I think the final paragraph could benefit from further explanation on specific genes related to antioxidant defense.