Ketone Bodies


Ketone Bodies

    • Ketone body synthesis and utilization
      • Synthesis of ketone bodies
        • occurs in liver mitochondria(MCQ)
        • occurs when fatty acids are in high concentration in the blood (during  fasting, starvation, or as a result of a high-fat diet).(MCQ)
        • How is Acetyl CoA accumulated during starvation
          • beta-Oxidationproduces NADH and ATP and results in the accumulation of acetyl coenzyme A (CoA), owing to allosteric inhibition of tricarboxylic acid (TCA) cycle enzymes. (MCQ)
          • The liver is also producing glucose using oxaloacetate (OAA), so there is decreased condensation of acetyl CoA with OAA to form citrate.(MCQ)
        • Two molecules of acetyl CoA condense to produce acetoacetyl CoA.
          • Enzyme :thiolase
        • Acetoacetyl CoA and acetyl CoA form hydroxymethylglutaryl CoA (HMG-CoA)
          • Enzyme :HMG-CoA synthase.(MCQ)
        • HMG-CoA is cleaved to form acetyl CoA and acetoacetate.
          • Enzyme :HMG-CoA lyase
        • Acetoacetate can be reduced  to3-hydroxybutyrate (also known as beta-hydroxybutyrate).
          • Enzyme :NAD-requiring dehydrogenase (3-hydroxybutyrate dehydrogenase)
          • This is a reversible reaction.
        • Acetoacetate is also spontaneously decarboxylatedin a nonenzymatic reaction, formingacetone
        • Acetone causes odor on the breath of ketotic diabetic patients
        • The liver lacks the enzyme needed to metabolize ketone bodies (succinyl CoA-acetoacetate- CoA transferase, a thiotransferase), so it cannot use the ketone bodies it produces. (MCQ)
        • Therefore, acetoacetate and 3-hydroxybutyrate are released into the blood by the liver.
      • Utilization of ketone bodies
        • When ketone bodies are released from the liver into the blood, they are taken up by peripheral tissues such as muscle and kidney, where they are oxidized for energy.
        • During starvation, ketone bodies in the blood increase to a level that permits entry into brain cells, where they are oxidized.(MCQ)
        • Acetoacetate can enter cells directly,
        • Acetoacetate can be produced from the oxidation of Beta-hydroxybutyrate(MCQ)
          • Enzyme :3-hydroxybutyrate dehydrogenase.
          • NADH is produced by this reaction and can generate ATP
        • Acetoacetate is activated by reacting with succinyl CoA to form acetoacetyl CoA and succinate.
          • Enzyme :succinyl CoA-acetoacetate-CoA transferase (a thiotransferase).
        • Acetoacetyl CoA is cleaved to form two molecules of acetyl CoA, which enter the TCA cycle and are oxidized to molecules of CO2.
          • Enzyme :thiolase
      • Energy Calculations on ATP produced during oxidation of ketone bodies.
          • One acetoacetate produces two acetyl CoA, each of which can generate about 10 ATP,or a total of about 20 ATP via the TCA cycle.(MCQ)
          • Why does activation of acetoacetate results in the generation of one less ATP?(MCQ)
            • Because guanosine triphosphate (GTP), the equivalent of ATP, is not produced when succinyl CoA is used to activate acetoacetate.
            • Whereas ,in the TCA cycle, when succinyl CoA forms succinate, GTP is generated
            • Therefore, the oxidation of acetoacetate produces a netyield of only 19 ATP
          • When 3-hydroxybutyrate is oxidized, 2.5 additional ATP are formed because the oxidation of 3-hydroxybutyrate to acetoacetateproduces NADH.(MCQ)

          20.       3-Hydroxy butyrate is formed by the reduction of:

          A.        Acetone

          B.        Aceto acetyl CoA

          C.        Acetoacetate

          D.        HMG CoA

          ANS:   20.       C. HMG CoA will be cleaved to acetoacetone and acetyl CoA. 3-hydroxybutyrate is formed by the reduction of acetoacetate, formation of 3-hydroxy butyrate depends on the availability of NADH. The spontaneous decarboxylation of acetoacetone forms acetone. Acetoacetate is reduced by a dehydrogenease to 3-hydroxybutyrate. Acetoacetate and acetone are known as ketone bodies. Out of the three, 3-hydroxybutyrate exists in high concentration.


          21.       Which enzyme is absent to utilize ketone bodies in liver:

          A.        3-Hydroxybutyrate dehydrogenase

          B.        3-Keto acetyl CoA transferase

          C.        Thiolase

          D.        HMGCoALyase

          ANS:   21.       B. In utilization of ketone bodies acetoacetate is formed by oxidation of 3-hydroxybutyrate. For the activation of acetoacetate coenzyme A is donated by succinyl CoA to from acetoacetyl CoA. This reaction is catalyzed by the enzyme 3-ketoacyl CoA transferase, which is absent in liver, that is a reason why liver cannot oxidize ketone bodies. Thiolase cleaves acetoacetyl CoA into two molecules of acetyl CoA, which enter the TCA cycle to produce energy. HMG CoA lyase enzyme helps in ketone bodies synthesis.


          22.       Ketone bodies:

          A.        Principle energy source for red blood cells.

          B.        Brain utilizes ketone bodies as its energy in well fed state

          C.        Mainly synthesised in starvation and uncontrolled diabetes

          D.        Synthesized from acetyl CoA in liver cytosol

          ANS:   22.       C. Ketone bodies are synthesized in liver mitochondria from acetyl CoA. Because of the absence of mitochondria RBC’s cannot metabolise ketone bodies. Brain utilizes glucose as its energy in well fed state. In starvation and uncontrolled diabetes ketone bodies are utilized to meet energy needs. Low levels of ketone bodies are produced all the time.


          23.       How many ATPs are yielded by oxidation of P-hydroxybutyrate:

          A.        23 moles of ATP        

          B.        26 moles of ATP

          C.        24 moles of ATP        

          D.        20 moles of ATP

           ANS:  23.       B. One mole of acetyl CoA- TCA cycle- electron transport chain =12 ATP

                      P-hydroxybutyrate- Acetoacetate – releases one NADH – electron transport chain = 3 ATP

                      2 Acetyl CoA are produced by oxidation of p-hydroxybutyrate.

                      The activation and oxidation of p-hydroxybutyrate requires             = -lATP

                      Conversion of p-hydroxybutyrate to acetoacetate releases one NADH molecule – electron transfer chain = 3ATP

                      2molecules Acetyl CoA is produced by p-hydroxy butyrate oxidation.

                      2Acetyl CoA molecules on oxidation by TCA cycle = 24 ATP

                      Net gain of total ATP by oxidation of p-hydroxybutyrate is 26ATP.

                      Oxidation of acetoacetate yields 23 moles of ATP.

          Ketone Bodies: Types and Function
          This video looks into ketone bodies and their function. These include the Acetoacetate, 3hydroxybutyrate and Acetone. It also looks into the benefits of ketone bodies and how they are used by the body.
          Human Metabolism Map VIII – Ketone Body Production
          Ketone body production from acetyl Coa and its use.
          Production of Ketone Bodies
          What are Ketones?
          Ketones are an acid that is the product of when the body burns its own fat. When the body don’t get enough glucose from the blood to use as energy, it burns fat.
          Ketones can be tested for with urine sticks or some blood glucose meters that also test for ketones.
          The build up of ketones is dangerous and Sue Marshall talks about the ins and outs of ketones.
          Ketone bodies
          Ketone bodies are three water-soluble molecules that are produced by the liver from fatty acids during periods of low food intake (fasting) or carbohydrate restriction for cells of the body to use as energy instead of glucose. Two of the three are used as a source of energy in the heart and brain while the third (acetone) is a degradation breakdown product of acetoacetic acid. Radioactive tracing of acetone determines that between 2% and 30% is excreted from the body. Ketone bodies are picked up by cells and converted back into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy. In the brain, ketone bodies are also used to make acetyl-CoA into long chain fatty acids because long chain fatty acids cannot pass through the blood-brain barrier. The liver also additionally produces glucose from non-carbohydrate sources except fatty acids by a process called gluconeogenesis during starvation. In the brain, ketone bodies are a vital source of energy during fasting or strenuous exercise. Although termed “bodies”, they are molecules, not particles.
          The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric acid. Other ketone bodies such as beta-ketopentanoate and beta-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides such as triheptanoin.