D-3-Hydroxybutyrate Dehydrogenase

Justine Cole and Hailey Moss

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I. Introduction

D-3-hydroxybutyrate dehydrogenase (HBDB) is an enzyme, found in the inner surface of the inner mitochondrial membrane, that catalyzes the oxidation of the reversible conversion between d-3-hydroxybutyrate and acetoacetate using NAD(+) as a coenzyme. HBDB is a lipid-dependent enzyme; in the absence of lipids, the enzyme is inactive.

The spontaneous decarboxylation of acetoacetate forms acetone as a product. Acetoacetate, acetone, and d-3-hydroxybutyrate are collectively referred to as ketone bodies. The brain, kidney and heart use ketone bodies, which are water-soluble compounds, as energy sources. They are synthesized in the liver from acetyl-CoA when carbohydrate metabolism is impaired. During starvation and intense exercise, HBDB can convert d-3-hydroxybutyrate and acetoacetate back into two molecules of acetyl-CoA, which enters and becomes the main energy source in the TCA cycle. 

It is also widely used by humans in patients with diabetes to detect the presence of ketone bodies, which may be associated with diabetic ketoacidosis. This is useful due to diabetes being a major physiological cause of elevated blood ketone levels.

II. General Structure

D-3-hydroxybutyrate dehydrogenase consists of 1,040 residues with a total molecular weight of 114.8 kDa . HBDH is composed of four identical subunits, each containing 260 amino acids: A, B, C, and D . (For more accurate viewing, only subunit A will be used to show the following residues and molecular interactions). Their binding geometries suggest that the reversible reactions occur by shuttle movements of a hydrogen negative ion from the C3 atom of the substrate to the C4 atom of
and from the C4 atom of
to the C3 atom of the product. The reaction might be further coupled to the withdrawal of a proton from the hydroxyl group of the substrate by the ionized Tyr155 residue.  

Figure.1 HBDH is the enzyme involved in the first reaction of this image. Substrate is B-hydroxybutyrate and H ion shuttled to NAD+, then from NADH to the product, Acetoacetate. Reaction is catalyzed by HBDH.

III. Substrate Binding

Substrate is promoted by a variety of molecular interactions. The first occurs with the carboxylate oxygen atom of the substrate which is bound to Gln94 and Gln196 through two hydrogen bonds which bind the acetate carboxylate group as well. The other substrate oxygen atom forms two hydrogen bonds with His144 and Lys152 . Tyr155 and Ser142 form the hydrophobic cavity for substrate binding, with the addition of two C atoms in the void space between the water O atom and the methyl group of acetate . HBDH also accommodates the methyl group of the substrate for substrate binding by occupying a small space surrounded by hydrophobic interactions with His144, Trp187 and Trp257 . The combined interactions are depicted here: .

IV. Optimal Isomer - Open and Closed Complex of HBDH

Substrate recognition coincides with the open-closed complex of HBDH. Hydrogen bonding between Gln196 and the carbonyl group of the substrate (or the inhibitor) is vital for creating a stable complex . Although the usual conformation is the open- form complex, when the closed-form conformation takes shape it is considered the active form of catalysis. Inhibitor binding encourages the changing open-closed conformational state of HBDH, and is influenced by Thr190 . Formation of hydrogen bonds between Thr190 and the carboxamide of NAD(+) is a significant factor involved in the changing open-closed complex .

V. Cofactor Binding


NAD+ and NADH binding occur by shuttling hydrogen negative ions from the C3 atom of the substrate (Beta-Hydroxybutyrate) to the C4 atom of NAD+ and from the C4 atom of NADH to the C3 atom of the product (acetoacetate). The cofactor is then anchored in the hydrophobic cavity surrounded by Ile16 , Ile140, Pro185 , Val188, and Val193 . This shuttling of hydrogen ions is what enables the enzymatic function of HBDH and the conversion of B-Hydroxybutyrate to acetoacetate.

VI. Relation to the World


D-3-hydroxybutyrate dehydrogenase is crucial to the conversion of ketone bodies into Acetyl CoA and the subsequent movement of Acetyl CoA into the Citric Acid Cycle. This is an important process for use as energy in the absence of sufficient glucose. It is also widely used by humans in patients with diabetes to detect the presence of ketone bodies, which may be associated with diabetic ketoacidosis. This is useful due to diabetes being a major physiological cause of elevated blood ketone levels.

VII. References

Bank, R. P. D. (n.d.). RCSB PDB - 3VDR: Crystal structure of D-3-hydroxybutyrate dehydrogenase, prepared in the presence of the substrate D-3-hydroxybutyrate and NAD(+). Retrieved November 28, 2022, from https://www.rcsb.org/structure/3VDR

Hoque, M. M., Shimizu, S., Juan, E. C. M., Sato, Y., Hossain, M. T., Yamamoto, T., Imamura, S., Suzuki, K., Amano, H., Sekiguchi, T., Tsunoda, M., & Takenaka, A. (2009). Structure of d-3-hydroxybutyrate dehydrogenase prepared in the presence of the substrate d-3-hydroxybutyrate and NAD+. Acta Crystallographica Section F: Structural Biology and Crystallization Communications, 65(Pt 4), 331–335. https://doi.org/10.1107/S1744309109008537

Hoque, M. M., Shimizu, S., Hossain, M. T., Yamamoto, T., Imamura, S., Suzuki, K., Tsunoda, M., Amano, H., Sekiguchi, T., & Takenaka, A. (2008). The structures of Alcaligenes faecalis D-3-hydroxybutyrate dehydrogenase before and after NAD+ and acetate binding suggest a dynamical reaction mechanism as a member of the SDR family. Acta Crystallographica. Section D, Biological Crystallography, 64(Pt 5), 496–505.

Ketone Bodies. (n.d.). Retrieved from https://journals.sagepub.com/cms/10.1038/sj.jcbfm.9600543/asset/images/large/10.1038_sj.jcbfm.9600543-fig1.jpeg.

3 3 hydroxybutyrate dehydrogenase An overview | sciencedirect topics. (n.d.). Retrieved November 28, 2022, from https://www.sciencedirect.com/topics/neuroscience/3-hydroxybutyrate-dehydrogenase

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