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Q.- What  are  the causes  of hypoglycemia and hypo ketosis in carnitine deficiency ?



The sources of glucose in normal health are-

1) Diet

2) Glycogen degradation

3) Gluconeogenesis

Dietary supply is sporadic and glycogen stores are sufficient only for 12-16 hours. The main supply of glucose is through gluconeogenesis in conditions of increased demand .

Carnitine deficiency causes Impaired gluconeogenesis  due to impaired beta oxidation of fatty acids since there is-

a) Insufficient  energy – Low ATP

b) Impaired activity of Pyruvate carboxylase- Acetyl co A is a positive allosteric modifier of Pyruvate carboxylase. In conditions of impaired fatty acid oxidation, Acetyl co A pool is small enough to sufficiently  activate pyruvate carboxylase. as a result there is less formation of Oxaloacetate and decrease rate of gluconeogenesis.

Thus hypoglycemia in carnitine deficiency is basically due to an imbalance between demand and supply of glucose. The demand is more, since the energy needs are fulfilled by glucose oxidation only.

Hypo ketosis- Impaired beta oxidation in carnitine deficiency results in less of Acetyl co A to be used for ketogenesis.



















Figure-1- showing the role of Acetyl co A as a positive allosteric modifier for Pyruvate carboxylase enzyme.


Q.2- Discuss in brief about the disorders associated with impaired  beta oxidation of fatty acids.

Answer- 1) Carnitine deficiency and deficiencies of CAT-1 and CAT-2 enzymes (Separately explained)

2) Jamaican Sickness- Jamaican vomiting sickness is caused by eating the unripe fruit of the akee tree, which contains the toxin hypoglycin, which inactivates medium- and short-chain acyl-CoA dehydrogenase, inhibiting β oxidation and causing hypoglycemia.

3) Dicarboxylic aciduria is characterized by the excretion of C6–C10 -dicarboxylic acids and by nonketotic hypoglycemia, and is caused by a lack of mitochondrial medium-chain acyl-CoA dehydrogenase.

4) Acute fatty liver of pregnancy- Acute fatty liver of pregnancy usually manifests in the second half of pregnancy, usually close to term, but may also develop in the postpartum period. The patient developed symptoms of hepatic dysfunction at 36 weeks of gestation. Short history of illness, hypoglycemia, liver failure, renal failure, and coagulopathy , all are observed  in Acute fatty liver of pregnancy, Typically, diagnosis is made based on an incidental finding of abnormal liver enzyme levels. Affected patients may become jaundiced or develop  encephalopathy  from liver failure, usually reflected by an elevated ammonia level. Profound hypoglycemia is common.

Q.- Discuss the oxidation of odd chain and unsaturated fatty acids.


1) oxidation of odd chain fatty acids- Fatty acids with an odd number of carbon atoms are oxidized by the pathway of β-oxidation, producing acetyl-CoA, until a three-carbon (propionyl-CoA) residue remains (Figure-2). This compound is converted to succinyl-CoA, a constituent of the citric acid cycle (Figure 3).











Steps of conversion of propionyl co A to Succinyl co A-

Propionyl-CoA is carboxylated at the expense of the hydrolysis of an ATP to yield the d isomer of methylmalonyl CoA (Figure 3). This carboxylation reaction is catalyzed by propionyl CoA carboxylase, a biotin dependent  enzyme that is homologous to and has a catalytic mechanism like that of pyruvate carboxylase. The d isomer of methylmalonyl CoA is racemized to the l isomer, the substrate for a mutase that converts it into succinyl CoA by an intramolecular rearrangement. This isomerization is catalyzed by methylmalonyl CoA mutase, which contains a derivative of vitamin B12, cobalamin, as its coenzyme.










Figure-3-Showing the conversion of propionyl co A to Succinyl co A. Propionyl CoA, generated from fatty acids with an odd number of carbons as well as from some amino acids, is converted into the citric acid cycle intermediate succinyl CoA.

 Deficiency of Vitamin B12 causes Methyl malonic aciduria.

Hence, the propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is glucogenic. Acetyl CoA  cannot be converted into pyruvate or oxaloacetate in animals. The two carbon atoms of the acetyl group of acetyl Co A enter the citric acid cycle, but two carbon atoms leave the cycle in the decarboxylations catalyzed by isocitrate dehydrogenase and a-ketoglutarate dehydrogenase. Consequently, oxaloacetate is regenerated, but it is not formed de novo when the acetyl unit of acetyl CoA is oxidized by the citric acid cycle.

Acetyl co A cannot be converted to Pyruvate since the reaction  catalyzed by Pyruvate dehydrogenase complex for the conversion of pyruvate to Acetyl co A is irreversible.

Oxidation of unsaturated fatty acids

 In the oxidation of unsaturated fatty acids , most of the reactions are the same as those for saturated fatty acids, only two additional enzymes an isomerase and a reductase are needed to degrade a wide range of unsaturated fatty acids.

 For example In the oxidation of palmitoleate,  C16 unsaturated fatty acid, which has one double bond between C-9 and C- 10, is activated and transported across the inner mitochondrial membrane in the same way as saturated fatty acids.

Palmitoleoyl  Co A then undergoes three cycles of degradation, which are carried out by the same enzymes as in the oxidation of saturated fatty acids. However, the cis-D 3-enoyl CoA formed in the third round is not a substrate for acyl CoA dehydrogenase. The presence of a double bond between C-3 and C-4 prevents the formation of another double bond between C-2 and C-3. This impasse is resolved by a new reaction that shifts the position and configuration of the cis-D 3 double bond. An isomerase converts this double bond into a trans- D 2 double bond. The subsequent reactions are those of the saturated fatty acid oxidation pathway, in which the trans- D 2-enoyl CoA is a regular substrate (Figure-4)



















Figure-4-Showing the oxidation of Palmitoleoyl co A, mono unsaturated fatty acid.

 A different set of enzymes  is required for the oxidation of Linoleic acid. a C18 polyunsaturated fatty acid with cis-Δ 9 and cis-Δ 12 double bonds (Figure 5). The cis- Δ 3 double bond formed after three rounds of  β oxidation is converted into a trans- Δ 2 double bond by the a aforementioned isomerase. The acyl CoA produced by another round of β oxidation contains a cis- Δ 4 double bond. Dehydrogenation of this species by acyl CoA dehydrogenase yields a 2,4-dienoyl intermediate, which is not a substrate for the next enzyme in the β -oxidation pathway. This impasse is circumvented by 2,4-dienoyl CoA reductase, an enzyme that uses NADPH to reduce the 2,4-dienoyl intermediate to trans-D 3-enoyl CoA. cis-Δ 3-Enoyl CoA isomerase then converts trans– Δ 3-enoyl CoA into the trans- Δ 2 form, a customary intermediate in the beta-oxidation pathway.. Only two extra enzymes are needed for the oxidation of any polyunsaturated fatty acid. Odd-numbered double bonds are handled by the isomerase, and even-numbered ones by the reductase and the isomerase.




















Figure-5- Showing the Oxidation of Linoleoyl CoA. The complete oxidation of the diunsaturated fatty acid linoleate is facilitated by the activity of enoyl CoA isomerase and 2,4-dienoyl CoA reductase.

Energy yield is less by the oxidation of unsaturated fatty acids since they are less reduced. Per double bonds 2 ATP are less formed, since the first step of dehydrogenation to introduce double bond is not required, as the double is already existing, FADH2 is not formed, and hence loss of 2 ATP per pre -existing double bond.


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