Diabetic ketoacidosis- Enzyme for ketones formation?

Case details

A 54- year-old man with Type 1 diabetes is referred to an ophthalmologist for evaluation of developing cataract. Blood chemistry results are shown below-

Fasting blood glucose   198 mg/dl

Hemoglobin A                  15 gm/dl

Hemoglobin A 1c             10% of total Hb

Urine ketones                   Positive

Urine glucose                    Positive

Which of the following enzymes is most strongly associated with ketones formation in this patient?

A) Pyruvate dehydrogenase complex

B) Thioesterase

C) Thiophorase

D) Thiokinase

E) Thiolase.

The correct answer is- E- Thiolase.

Out of the given options thiolase is the only enzyme involved in the ketogenesis. The process of ketogenesis starts from the action of thiolase.  In fact, the actual specific enzyme for ketogenesis is HMG Co A Synthase (mitochondrial isoform) which is not mentioned in the given options.

Ketone bodies

Acetoacetate, D (-3) -hydroxybutyrate (Beta hydroxy butyrate), and acetone are often referred to as ketone bodies (figure-1).

Ketone bodies

Figure-1- Acetoacetate is the primary ketone body, the other ketone bodies are derived from it.

The term “ketones” is actually a misnomer because beta-hydroxybutyrate is not a ketone and there are ketones in blood that are not ketone bodies, e.g., pyruvate, fructose.

Ketogenesis takes place in liver using Acetyl co A as a substrate or a precursor molecule. Enzymes responsible for ketone body formation are associated mainly with the mitochondria.

Steps of synthesis

Acetoacetate (First ketone body) is formed from acetyl CoA in three steps (Figure-2).

1) Two molecules of acetyl CoA condense to form Acetoacetyl CoA. This reaction, which is catalyzed by thiolase, is the reverse of the thiolysis step in the oxidation of fatty acids.

2) Acetoacetyl CoA then reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA.  The reaction is catalyzed by HMG co A synthase. This enzyme is exclusively present in liver mitochondria. There are two isoforms of this enzyme-cytosolic and mitochondrial. The mitochondrial enzyme is needed for ketogenesis while the cytosolic form is associated with cholesterol biosynthesis.

3)3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate in the presence of HMG Co A lyase (Figure-2)

The other two ketone bodies-Acetone and D (-) – 3-Hydroxybutyrate are formed from Acetoacetate, the primary ketone body.

4) Acetone is formed by decarboxylation in the presence of decarboxylase enzyme and, because it is a beta-keto acid, acetoacetate also undergoes a slow, spontaneous decarboxylation to acetone. The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate in the blood.  “Acetone-breath” has been used as  a  crude  method  of  diagnosing  individuals  with  untreated Type  I  diabetes mellitus.

5) D (-)-3-Hydroxybutyrate is formed by the reduction of acetoacetate in the mitochondrial matrix by D (-) 3-hydroxybutyrate dehydrogenase.


Figure-2- steps of ketogenesis

As regards other options

Pyruvate dehydrogenase complex– catalyzes the conversion of pyruvate to Acetyl co A.

Thioesterase- Catalyzes the release of newly synthesized fatty acid from the active site of fatty acid synthase complex.

Thiophorase is required for the utilization of ketone bodies.

Thiokinasecatalyzes the activation of free fatty acid to fatty acyl co A prior to fatty acid oxidation.

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