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Problem based questions

1. A full-term female infant failed to gain weight and showed metabolic acidosis in the neonatal period. A physical examination at 6 months showed failure to thrive, hypotonia, small muscle mass, severe head lag, and a persistent acidosis (pH 7.0 to 7.2). Blood lactate, pyruvate, and alanine were greatly elevated. Treatment with thiamine did not alleviate the lactic acidosis. Which of the following enzymes is most likely deficient in this patient?

a) Alanine amino transferase

b) Phosphoenolpyruvate carboxy kinase

c) Pyruvate carboxylase

d) Pyruvate dehydrogenase

e) Pyruvate kinase

 The right answer is- d)

The symptoms are suggestive of Pyruvate dehydrogenase complex deficiency. Pyruvate dehydrogenase complex (PDC) deficiency (PDCD) is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism.

Pyruvate dehydrogenase, a multienzyme complex, catalyzes the conversion of pyruvate to acetyl co A. The major fate of Acetyl co A is oxidation in citric acid cycle, which is a chief metabolic cycle to derive energy from carbohydrates. Malfunction of this cycle deprives the body of energy. The impaired conversion of pyruvate to Acetyl co A leads to elevation of blood pyruvate, lactate and alanine. The persistent metabolic acidosis is due to accumulation of lactates in blood that results in nonspecific symptoms (e.g., severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake. Similar symptoms though mild in nature can also be observed in Thiamine deficiency, as TPP is requires as a coenzyme for PDH complex. Since in the given case the patient is resistant to supplementation with thiamine, the deficiency of thiamine is ruled out.

Alanine transferase catalyzes the conversion of pyruvate to alanine (transamination). It cannot be the defect as alanine levels are also elevated.

 Phospho enol pyruvate carboxy kinase catalyzes the conversion of Oxaloacetate to phosphoenol pyruvate. The deficiency is rare.

Pyruvate carboxylase catalyzes the conversion of pyruvate to oxaloacetate.

Pyruvate kinase catalyzes the conversion of phosphoenol pyruvate to pyruvate.

The clinical manifestations in the given case are only suggestive of PDH complex deficiency.

2. A 3- year-old female child whose growth rate has been in the lower 10th percentile over the last year presents with chronic, nonproductive cough and diarrhea with foul-smelling stools. She is diagnosed as having cystic fibrosis. For which of the following vitamins is this child most likely to be at risk of deficiency?

a)  Vitamin C

b) Vitamin B6

c) Folic acid

d) Retinol (vitamin A)

e) Riboflavin (vitamin B2)

The right answer is- d) – Cystic fibrosis, is an autosomal recessive disorder affecting approximately 1 in 2500 white individuals. It is caused due to defective chloride ion channels of exocrine glands and epithelial tissues involving pancreas, sweat glands, and mucous glands in the respiratory, digestive, and reproductive tracts. Affected patients usually have abnormal mucus secretion resulting in recurrent respiratory infections, gastrointestinal obstruction and pancreatic enzyme dysfunction.

The protein cystic fibrosis transmembrane conductance regulator (CFTR) is defective, leading to abnormal chloride transport. Because cystic fibrosis leads to pancreatic damage and diminution of the ability to secrete HCO3− and pancreatic digestive enzymes, as a result fat and protein are absorbed poorly. Retinol is a fat soluble vitamin that must be absorbed along with lipid micelles; hence the absorption of retinol is grossly affected.  The absorption of other fat-soluble vitamins E, D, and K is also decreased.

Vitamins C, B6, folic acid and riboflavin are water-soluble vitamins and their absorption is not significantly affected.

3. A 54-year-old male who was diagnosed with HIV (human immuno deficiency virus) infection 2 years back, is currently in the terminal stage. He is now cachectic and having a difficult time obtaining any caloric intake yet he refuses to take a naso gastric or gastric feeding tube. Since his muscle and organs are metabolically active, which of the following amino acids will produce both glucose and ketone bodies as an energy source?

a) Alanine

b) Tyrosine

c) Proline

d) Glycine

e) Leucine

The right answer is b) Tyrosine.

Tyrosine is the only amino acid in the given options that is both glucogenic as well as ketogenic. Upon metabolism tyrosine produce one molecule of fumarate and one molecule of acetoacetate. Fumarate is converted to Oxaloacetate (through intermediate formation of malate) which can be converted to glucose. Acetoacetate is cleaved to form 2 molecules of acetyl co A under the effect of Thiolase enzyme.  Since Acetyl co A is a precursor of ketone bodies, thus it represents the ketogenic component of Tyrosine.

Alanine can be transaminated to pyruvate (catalyzed by alanine transferase) which can be channeled towards the pathway of gluconeogenesis, thus it is purely glucogenic.

Proline upon metabolism produces Alpha ketoglutarate, a TCA cycle intermediate that can be converted to oxaloacetate and thus it is glucogenic.

Glycine is also purely glucogenic. Glycine is converted to serine that produces pyruvate by non oxidative deamination.

Leucine is purely ketogenic. Upon metabolism it produces acetoacetate and acetyl CoA, both are ketogenic fractions.

4. A 40 -year-old man presents with chest pain that radiates to his left jaw and shoulder. He is diagnosed with a myocardial infarct (heart attack) and is prescribed a statin medication. Statins are competitive inhibitors of HMG CoA reductase, which converts HMG Co A to which of the following?

a) Isopentenyl pyrophosphate

b) Mevalonate

c) Geranyl pyrophosphate

d) Farnesyl pyrophosphate

e) Cholesterol

The right answer is- b) Mevalonate.

The reaction catalyzed by HMG Co A reductase is the principal regulatory step in the pathway of cholesterol synthesis and is the site of action of the most effective class of cholesterol-lowering drugs, the HMG-CoA reductase inhibitors (statins). )

Isopentenyl pyrophosphate is formed from Mevalonate. Mevalonate is phosphorylated sequentially by ATP by three kinases, and after decarboxylation the active isoprenoid unit, Isopentenyl pyrophosphate (C5), is formed.

Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl pyrophosphate, then condensed with another molecule of Isopentenyl diphosphate to form the ten-carbon intermediate Geranyl pyrophosphate (C10).

A further condensation of Geranyl pyrophosphate (C10) with Isopentenyl pyrophosphate forms Farnesyl pyrophosphate (C15). Cholesterol is the final product of the pathway.

5. Which of the following compounds is the direct precursor for the heme nitrogen atoms?

a) Glucose

b) Glycine

c) Succinyl co A

d) Alanine

e) Methionine

The right answer is- b) Glycine.

Heme is synthesized in living cells by a pathway that requires Succinyl-CoA, derived from the citric acid cycle in mitochondria, and the amino acid glycine. The product of the condensation reaction between Succinyl-CoA and glycine is α-amino-β-ketoadipic acid, which is rapidly decarboxylated to form -δ-amino levulinate (ALA). Through a number of further steps Heme is synthesized.

Glucose does not have nitrogen in its structure to contribute towards heme formation, whereas alanine and methionine do possess amino groups but they do not contribute to Heme nitrogen.

6. A pregnant woman is able to transfer oxygen to her fetus because fetal hemoglobin has a greater affinity for oxygen than does adult hemoglobin. Why is the affinity of fetal hemoglobin for oxygen higher?

a) The tense form of hemoglobin is more prevalent in the circulation of the fetus.

b) There is less 2, 3-BPG in the fetal circulation as compared to maternal circulation.

c) Fetal hemoglobin binds 2, 3-BPG with fewer ionic bonds than the adult form.

d) The Bohr effect is enhanced in the fetus.

e) The oxygen-binding curve of fetal hemoglobin is shifted to the right.

The right answer is -c). The enhanced uptake of maternal oxygen by fetal Hb is due to less binding of 2, 3 BPG with fetal Hb.

It is not due to more prevalence of tense form of fetal hemoglobin in the circulation.

It is also not due to less 2, 3 BPG in the fetal circulation, the Bohr Effect is not enhanced in the fetus and the oxygen -binding curve of fetal Hb is also not shifted to the right.

In Hb A (adult Hb) when 2, 3-BPG binds to deoxyhemoglobin, it acts to stabilize the low oxygen affinity state (T state) of the oxygen carrier, exploiting the molecular symmetry and positive polarity by forming salt bridges with lysine and histidine residues in the four subunits of hemoglobin.

The R state, with oxygen bound to a heme group, has a different conformation and does not allow this interaction. By selectively binding to deoxyhemoglobin, 2, 3-BPG stabilizes the T state conformation, making it harder for oxygen to bind hemoglobin and more likely to be released to adjacent tissues.

Fetal hemoglobin (HbF) exhibits a low affinity for 2, 3-BPG, resulting in a higher binding affinity for oxygen. This increased oxygen-binding affinity relative to that of adult hemoglobin (HbA) is due to HbF’s having two α/γ dimers as opposed to the two α/β dimers of HbA. The positive histidine residues of HbA β-subunits that are essential for forming the 2, 3-BPG binding pocket are replaced by serine residues in HbF γ-subunits so 2, 3-BPG has difficulties in linking to the fetal hemoglobin, hence the affinity of fetal hemoglobin for O2 increases. That’s the way O2 flows from the mother to the fetus.

7. A 35-year-old female presents with severe dehydration and decreased urine output. Her blood urea nitrogen level is abnormally elevated because her kidneys are not able to excrete urea in the urine. In the production of urea, which of the following is an important intermediate?

a) Serine

b) Glutamate

c) Proline

d) Ornithine

e) Leucine

The right answer is-d) Ornithine

Urea is the end product of nitrogen/amino acid metabolism. Urea formation requires the participation of 6 amino acids which are aspartic acid, ornithine, citrulline, argino succinic acid, arginine and N-Acetyl glutamate. Out of these N -Acetyl glutamate is the only amino acid that acts as an allosteric activator of Carbamoyl phosphate synthase-1 enzyme, rest all participate in urea formation. Ornithine acts as a catalyst in the process of urea formation. Ornithine is a non standard amino acid, it is not incorporated in to tissue proteins but it participates in urea formation and polyamine synthesis.

Serine does not participate in urea formation. It is glucogenic, incorporated in to tissue proteins, required for synthesis of glycine, cysteine and sphingosine. Also participates in one carbon metabolism, forming O- glycosidic linkages and is present in at the active site of many enzymes.

Glutamate is a precursor of GABA, glutamine, glucogenic, a neurotransmitter and is incorporated in to tissue proteins. It does not participate in urea formation.

Proline also does not participate in urea formation; it is incorporated in to tissue proteins and is present at those places where kinks or bends are needed in the folding of the proteins since it is an imino acid. Collagen is rich in hydroxy proline (its hydroxylated form).

Leucine is a branched chain amino acid; it is purely ketogenic and has no role in urea formation.

8. Which of the following is a common compound shared by the TCA cycle and the urea cycle?

a) α-Keto glutarate

b) Argino succinic acid

c) Arginine

d) Fumarate

e) Aspartate

The right answer is- d) Fumarate.

Alpha ketoglutarate is an intermediate of TCA cycle; it has no connection with urea cycle.

Argino succinic acid is an intermediate of urea cycle and is formed by condensation of aspartic acid and Citrulline. It is not connected to TCA cycle, but upon breakdown it produces Arginine and fumarate. Fumarate is channeled towards TCA cycle. Fumarate is converted to malate and then to oxaloacetate through TCA cycle enzymes. Oxalo acetate is transaminated to form Aspartic acid that can be reutilized to form Argino succinic acid for continuation of urea cycle.

Aspartic acid is needed in urea formation but it is not an intermediate of TCA cycle.

Thus, Fumarate is the right answer.

9. Which enzyme often mal functions in diseases associated with the symptoms of high blood triglyceride levels and Steatorrhea?

a) Phospholipase D

b) Lipoprotein lipase

c) Thiokinase

d) Acetyl co A carboxylase

e) Pancreatic lipase

The right answer is- e) pancreatic lipase.

Steatorrhea occurs due to impaired digestion and absorption of lipids and other chief nutrients. It is characterized by passage of bulky stools and is often associated with deficiencies of fat soluble vitamins. Hypertriglyceridemia is a characteristic finding in Pancreatitis and there are several causes of Acute and chronic pancreatitis. In pancreatic disorders, pancreatic lipase deficiency results in impaired digestion of lipids as well as other nutrients causing Steatorrhea.

Phospholipase D enzyme is required for removal of nitrogenous base from phospholipid. It cannot cause the symptoms of high blood triglyceride levels and Steatorrhea.

Lipoprotein lipase is an enzyme for the degradation of triglacylglycerols present in chylomicrons and VLDL. Impaired activity can cause increase in serum triacylglycerol levels but Steatorrhea is unlikely to happen.

Thiokinase is the first enzyme of beta oxidation of fatty acids. It is required for the conversion of free fatty acid to fatty acyl co A (activation of fatty acid); it is also called Acyl Co A synthetase. This enzyme has nothing to do with lipid digestion or absorption and is not involved in the synthesis or degradation of triacylglycerols.

Acetyl co A carboxylase is an enzyme of fatty acid synthesis. It catalyzes the first step of conversion of acetyl co A to malonyl co A. It is the rate limiting step of de no fatty acid synthesis, malfunctioning of this enzyme cannot cause increase in TGs or Steatorrhea.

Thus the right answer is pancreatic lipase.

10. An infant is born with a high forehead, abnormal eye folds, and deformed ear lobes. He shows little muscle tone and movement. After multiple tests, he is diagnosed with Zellweger syndrome, a disorder caused by malformation of peroxisomes.
Which of the following is expected to be high in concentration in brain tissue of the affected individual?

a) Ketone bodies

b) Lactate

c) Cholesterol

d) Very long chain fatty acids

e) Glucose

The right answer is d), “Very long chain fatty acids”. Very long chain fatty acids are first trimmed in the peroxisomes till the length of C16 or C18, then they are transported to mitochondria in the conventional way though carnitine shuttle to be oxidized completely by beta oxidation.

Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder (present at birth), characterized by the reduction or absence of Peroxisomes in the cells of the liver, kidneys, and brain. In Zellweger syndrome the Peroxisomal trimming is impaired, thus VLFA accumulate in brain and blood of affected patients.

The option ketone body is ruled out because the above said symptoms are not characteristic of ketosis.

Lactate is also ruled out because excess of lactate (lactic acidosis) is also not a congenital disorder; lactate accumulates either due to non utilization (as in liver disorders) or excessive production (as in anaerobic conditions).

Cholesterol excess, hypercholesterolemia is also not the right option; the symptoms are suggestive of a congenital disorder that has affected the brain and physical growth. There is no such clinical state associated with hypercholesterolemia and impaired mental development.

Hyperglycemia is also not the right choice. Hyperglycemia is never associated with malformation of peroxisomes.

Hence the right option is very long chain fatty acids. For further details of Zellweger syndrome follow the link

http://www.namrata.co/minor-pathways-of-fatty-acids-oxidation-a-quick-review/

11. After excessive drinking over an extended period of time while eating poorly, a middle-aged man is admitted to the hospital with “high output” heart failure. Which of the following enzymes is most likely inhibited?

a) Aconitase

b) Citrate synthase

c) Isocitrate dehydrogenase

d) α-Ketoglutarate dehydrogenase

e) Succinate thiokinase

The right answer is d) – Alpha ketoglutarate dehydrogenase deficiency.

The patient is most probably suffering from cardiac beriberi. The criteria for diagnosing cardiac beriberi is- 1)  Signs of heart failure 2) signs of neuropathies 3) history of alcoholism or poor nutritional history, 4)exclusion of other signs of heart failure, 5) low red cell Transketolase activity 6) Response by thiamine administration.

The above said patient is a known alcoholic, mal nourished and has heart failure .The probable diagnosis is Thiamine deficiency, which can be confirmed by Erythrocyte Transketolase activity. Thiamine is required as a coenzyme for Pyruvate dehydrogenase complex, alpha ketoglutarate dehydrogenase complex, transketolase and alpha keto acid dehydrogenase complex.

Out of all the given options only alpha ketoglutarate dehydrogenase is the only enzyme which is Thiamine dependent and that could possibly be inhibited in beri-beri.

Aconitase is iron dependent enzyme of TCA cycle. All the enzymes enlisted are though enzymes of TCA cycle, but the deficiencies of Aconitase, citrate synthase, isocitrate dehydrogenase and succinate thiokinase are unknown. Alpha ketoglutarate dehydrogenases deficiency is unknown but its impaired activity is observed in thiamine deficiency. TCA cycle enzyme deficiencies are incompatible with life proving that TCA cycle is vital to life.

12. A 16-month-old girl was found to have ingested approximately 30 mL of an acetonitrile-based cosmetic nail remover when she vomited 15 minutes post ingestion. The poison control center was contacted, but no treatment was recommended because it was confused with an acetone-based nail polish remover. The child was put to bed at her normal time, which was 2 hours post ingestion. Respiratory distress developed sometime after the child was put to bed, and she was found dead the next morning.

Inhibition of which of the following enzymes was the most likely cause of this child’s death?

a) Cytochrome c reductase

b) Cytochrome oxidase

c) Coenzyme Q reductase

d) NADH dehydrogenase

e) Succinate dehydrogenase

 The right answer is-b) – Cytochrome oxidase.

 Acetonitrile is used mainly as a solvent. It is the chemical compound with the formula CH3CN. Acetonitrile has only a modest toxicity in small doses. It can be metabolized to produce hydrogen cyanide, which is the source of the observed toxic effects. Generally the onset of toxic effects is delayed, due to the time required for the body to metabolize acetonitrile to cyanide (generally about 2–12 hours). It has been used in formulations for nail polish remover, despite its low but significant toxicity. Acetone and ethyl acetate are often preferred as safer for domestic use, and acetonitrile has been banned in cosmetic products in the European Economic Area since March 2000.

Cyanide released from the metabolism of acetonitrile, is an inhibitor of Cytochrome oxidase. Electron flow in cytochrome c oxidase can be blocked by hydrogen sulphide (H2S), cyanide (CN-), azide (N3 -), and carbon monoxide (CO). Cyanide and azide react with the ferric form of heme a 3, whereas carbon monoxide inhibits the ferrous form. Inhibition of the electron-transport chain also inhibits ATP synthesis because the proton-motive force can no longer be generated.

The options given above represent the complexes of electron transport chain. There are site specific inhibitors for each of the complexes of electron transport chain. It is only cytochrome oxidase that is inhibited by Cyanide.

For further details- follow the link given below

http://www.namrata.co/inhibition-of-oxidative-phosphorylation/

 

 

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1. Which of the following enzymes is not present in adipose tissue?

a) Hexokinase

b) Glycerol kinase

c) Phosphofructokinase

d) Hormone sensitive lipase

e) Acetyl co A carboxylase

Answer- b) The right answer is Glycerol kinase. It is absent in adipose tissue, that is the reason glycerol released by hydrolysis of triglycerides cannot be reutilized there . It is a waste product. It is transported through blood to liver where it is first phosphorylated to form Glycerol-3-P, by glycerol kinase and then converted to Dihydroxy acetone phosphate by the action of glycerol-3-P dehydrogenase. DHAP can be either used for glucose production or oxidized through glycolysis as per the need. In adipose tissue glycerol-3-p is obtained through glycolysis from dihydroxy acetone phosphate for esterification to form triglyceride.

Hexokinase and Phosphofructokinase are enzymes of glycolytic pathway, they are present in muscle. Hormone sensitive lipase is the enzyme for breakdown of triglycerides; it is present in adipose tissue. Acetyl co A carboxylase is the rate limiting enzyme of fatty acid synthesis, it catalyzes the first step of conversion of acetyl co A to malonyl co A, and it is present in adipose tissue.

2. A postpartum woman from a rural community recently gave birth to a baby boy with the aid of a midwife at home. She now brings the baby to the hospital because of continued bleeding and oozing from the umbilical stump. It is likely that this bleeding diathesis is secondary to a deficiency of which vitamin?

a) Vitamin A

b) Vitamin K

c) Vitamin E

d) Vitamin D

c) Folic acid

The right answer is-b) Vitamin K. Newborn infants are at risk of developing vitamin K deficiency, and this coagulation abnormality leads to serious bleeding. Transplacental transfer of vitamin K is very limited during pregnancy, and the storage of vitamin K in neonatal liver is also limited. This makes the newborn infant uniquely vulnerable to hemorrhagic disorders unless exogenous vitamin K is given for prevention of bleeding immediately after birth.

Vitamin A has a role in vision, repair, reproduction and maintenance of epithelial structures. Deficiency is known to cause ophthalmological defects leading eventually to blindness.

 Vitamin E is primarily an antioxidant and has also a role in reproduction.

Vitamin D – Its main function is in the regulation of calcium absorption and homeostasis. It has no role in coagulation of blood. Deficiency causes rickets in children and osteomalacia in adults.

Folic acid has a role in nucleotide synthesis and acts as a carrier of one carbon fragments. Deficiency causes megaloblastic anemia.

3. A 40- year-old male presents with excruciating pain in his left flank. He is diagnosed to have a kidney stone and is prescribed citrate to help prevent future stone formation. In the TCA cycle, Citrate is isomerized to Isocitrate and that is subsequently oxidized to α- Keto glutarate by Isocitrate dehydrogenase, a regulatory enzyme of TCA cycle. Which of the following would be most likely to inhibit Isocitrate dehydrogenase?

a) ADP

b) Acetyl co A

c) NADH

d) FADH2

e) Co ASH

Answer- The right answer is- c)

Isocitrate dehydrogenase is inhibited by excessive concentration of NADH. The three NAD+ dependent enzymes of TCA cycle; Isocitrate dehydrogenase, α-keto glutarate dehydrogenase and Malate dehydrogenase are inhibited by accumulation of NADH. Since three reactions of the TCA cycle as well as PDH utilize NAD+ as co-factor it is not difficult to understand why the cellular ratio of NAD+/NADH has a major impact on the flux of carbon through the TCA cycle. Thus, activity of TCA cycle is immediately dependent on the supply of NAD+, which in turn, is dependent upon the functioning of electron transport chain and oxidative phosphorylation.

It cannot be ADP, because ADP excess is a sign of low energy state of cell that in itself is a stimulus for the TCA activity to restore the energy balance. On the contrary excess ATP concentration  inhibits the TCA cycle (respiratory control of TCA cycle). Acetyl co A, in excess inhibits PDH complex, but it has no effect on activity of Isocitrate dehydrogenase. Since isocitrate dehydrogenase is NAD+ dependent enzyme, excess FADH2 will not affect the rate of action of enzyme. Similarly, Co ASH concentration can affect PDH complex, but it has no effect on isocitrate dehydrogenase activity.

4 . A 50-year-old female presents with severe abdominal pain. Her serum amylase and lipase levels are abnormally elevated and she is diagnosed with pancreatitis. Which linkage between glucose residues is cleaved by amylase ?

a) α- 1,4

b) α- 1,6

c) β-1,4

d) α 1,2

e) β-1,6

Answer- a) alpha – 1, 4 is the right answer.  Amylase acts on starch and glycogen to cleave α- 1, 4 glycosidic linkages. Both starch and glycogen are polymers of glucose. The two main constituents of starch  are amylose (13–20%), which has a nonbranching helical structure, and amylopectin (80–85%), which consists of branched chains composed of 24–30 glucose residues united by α-1,4 linkages in the chains and by α-1 .6 linkages at the branch points. Glycogen, a more highly branched structure than amylopectin contains chains of 12–14 α-D-glucopyranose residues (in α-1 ,4 glucosidic linkage) with branching by means of α-1 ,6 glucosidic bonds. Thus the branch point contains α- 1, 6 linkage that cannot be cleaved by amylase. Mammals lack any enzyme that hydrolyzes the β-1 ,4 bonds, and so cannot digest cellulose that consists of β-D-glucopyranose units linked by β-1 ,4 bonds to form long, straight chains strengthened by cross-linking hydrogen bonds. α 1,2 linkage, more precisely- O-α-D-glucopyranosyl-(1,2)-β -D-fructofuranoside linkage is found in sucrose that is hydrolyzed by sucraseβ-1,6 linkages are not common in nutrients.

5 . A 12-year-old -girl presents with polyuria, polydipsia and polyphagia. Blood Biochemistry reveals a glucose level of 320 mg/dl . She is diagnosed with Type 1 Diabetes mellitus, a disease characterized by a deficiency of Insulin. Which of the following would occur in this patient ?

a) Increased stores of triacylglycerol in adipose tissue

b) Deceased conversion of fatty acids to ketone bodies

c) Increased fatty acids synthesis from glucose in liver

d) Decreased synthesis of cholesterol in liver

e) Increased conversion of fatty acids to acetyl co A

Answer- The right answer is -e) Increased conversion of fatty acids to acetyl co A.  In diabetes mellitus, Insulin to glucagon ratio is reversed as a result there is a state of catabolism. Triglycerides stores in adipose tissue are decreased due to adipolysis under the influence of glucagon. In diabetes mellitus, de novo fatty acid synthesis in liver is deceased because in insulin deficiency the catalytic activity of Acetyl co A carboxylase (rate limiting – insulin dependent enzyme) is decreased, hence the overall pathway is inhibited. Cholesterol synthesis in diabetes mellitus is increased. It is expected that cholesterol synthesis would decrease in insulin deficiency since insulin stimulates the activity of HMG Co A reductase (rate limiting enzyme of cholesterol pathway), but on the contrary de novo cholesterol synthesis is increased.

In diabetes mellitus, due to non utilization of glucose, fatty acid oxidation takes place excessively to compensate for energy, as a result there is accumulation of acetyl co A (product of fatty acid oxidation). Excess acetyl co A (since TCA cycle is in a state of suppression) is channeled either towards ketogenic pathway or it is utilized for cholesterol synthesis. Uncontrolled diabetes mellitus is a commonest cause of hypercholesterolemia.

6. Which of the following is a compound formed from both a hydroxylation with an enzyme requiring vitamin C and subsequent methylation?

a) Histamine

b) GABA

c) Creatinine

d) Epinephrine

e) Serotonin

The right answer is-d) Epinephrine.

Neural cells convert tyrosine to epinephrine and norepinephrine. Tyrosine is first converted to DOPA by tyrosine hydroxylase enzyme. Dopa decarboxylase, a pyridoxal phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine β-oxidase then forms norepinephrine. In the adrenal medulla, phenyl ethanolamine-N-methyltransferase utilizes S-adenosylmethionine to methylate the primary amine of norepinephrine, forming epinephrine.

Gamma Amino butyrate (GABA) functions in brain tissue as an inhibitory neurotransmitter by altering transmembrane potential differences. It is formed by decarboxylation of glutamate, a reaction catalyzed by L-glutamate decarboxylase

Glycine, arginine, and methionine all participate in creatine biosynthesis. Synthesis of creatine is completed by methylation of guanidoacetate by S-adenosylmethionine. Creatinine is an anhydrous product of creatine.

Serotonin (5-hydroxytryptamine), a potent vasoconstrictor and stimulator of smooth muscle contraction, is formed by hydroxylation of tryptophan to 5-hydroxytryptophan followed by decarboxylation.

7. A deficiency of biotin in higher animal is likely to be accompanied by which one of the following:

a) Defective oxidation of fatty acids to Acetyl co A

b) Decreased conversion of pyruvate to Acetyl co A

c) Defective synthesis of fatty acids

d) Decreased utilization of Acetyl co A in TCA cycle

e) Decreased formation of lactic acid in muscles

Answer- The right answer is c) – Defective synthesis of fatty acids.

Biotin is mainly required as a coenzyme for carboxylation reactions and the main examples are carboxylation of-i) pyruvate to oxaloacetate (first step of gluconeogenesis); ii) Acetyl co A to Malonyl co A (first step of fatty acid synthesis) and iii) Propionyl co A to D-Methyl malonyl co A (in the conversion of propionyl co A to Succinyl co A to gain entry to TCA cycle). In biotin deficiency, out of the given options, defective fatty acid synthesis is the most suited option because of the impaired conversion of acetyl co A to malonyl co A.

Fatty acid oxidation does not require biotin; FAD and NAD+ are the required coenzymes in beta oxidation of fatty acids.

Biotin is also not needed as a coenzyme during the conversion of pyruvate to Acetyl co A. The enzyme complex, PDH complex catalyzing this reaction requires TPP, CoASH, Lipoic acid, FAD and NAD+ as coenzymes.

In the utilization of Acetyl co A in TCA cycle. biotin is not required as a coenzyme; FAD and NAD+ are required as coenzymes.

Formation of lactic acid in muscle takes place from pyruvate in a reaction catalyzed by lactate dehydrogenase which requires NADH as a coenzyme.

8 . A 54 -year-old Native- American living on an Indian reservation in southwest Arizona presents to the clinic with impaired memory, diarrhea and a rash on the face, neck, and dorsum of hands. It is likely that the patient has a deficiency of which of the following vitamins?
a) Niacin

b) Folic acid

c) Vitamin C

d) Vitamin E

e) Vitamin B6

Answer- The right answer is a)- Niacin.

The clinical manifestations in the present case are of ‘Pellagra’, that occurs due to niacin deficiency.

Pellagra is manifested by Dementia, diarrhea, dermatitis and ‘death’ in untreated cases (4Ds). Pellagra is a common finding in Maize eaters. Maize lacks tryptophan which is an endogenous source of niacin, besides that niacin is also present in the bound form in maize that is biologically unavailable. Hence maize eaters always carry a predisposition to niacin deficiency.

Folic acid deficiency causes megaloblastic anemia.

Vitamin C deficiency causes Scurvy,

 There is no specific disorder associated with Vitamin E deficiency, but generalized neurological symptoms and infertility have been found to be associated with vitamin E deficiency.

Deficiency of vitamin B6 is manifested by skin changes (pellagra), neurological changes and Sideroblastic anemia. Vitamin B6 is required as a coenzyme in the pathway of niacin synthesis from tryptophan. Hence B6 deficiency also leads to niacin deficiency.

9 . A 40-year-old man presents with severe pain in his legs upon walking. He is diagnosed with atherosclerotic plaques in the arteries of his legs. High level of cholesterol and LDL contribute to the formation of atherosclerotic plaques. Which of the following is metabolized to form LDL?

a) IDL

b) Cholesterol

c) Cholesteryl esters

d) HDL

e) Chylomicrons

The right answer is- a) IDL.

IDL is produced from the metabolism of VLDL and IDL is further processed to form LDL.

VLDL s are produced in the liver and are secreted directly in to the blood as nascent VLDLs containing apoprotein B-100. They obtain apo CII and apo E from HDL. Apo CII is required for the activation of lipoprotein lipase whereas apo E acts as a ligand for internalization through apo B100/apo E receptors.

As VLDLs pass through the circulation triacylglycerols are degraded by lipoprotein lipase, causing VLDLs to shrink in size and become denser. Initially apo CII is returned to HDL and VLDL is converted to IDL (intermediate density lipoprotein) or VLDL remnant. IDL can be either taken up by cells through receptor mediated endocytosis that uses apo E as a ligand or apo E is returned to HDL and IDL is converted to LDL (low density lipoprotein). The primary function of LDL is to provide cholesterol to the peripheral tissues.

Cholesterol cannot be the answer, since it is through lipoproteins only that cholesterol is transported to the peripheral tissues.

Cholesteryl esters are esterified forms of cholesterol. A fatty acid is esterified at 3-OH group of cholesterol. Plasma contains both free and esterified cholesterol.

HDL transports cholesterol from peripheral tissues back to liver for degradation, it is antiatherogenic; hence it is cardio protective also called “Good cholesterol”.

Chylomicrons are transporters of dietary lipids. Upon metabolism in the similar way as VLDL, they are converted to chylomicron remnants that are removed from the circulation by liver.

10 . A 5-year-old boy presents with altered mental status, heart failure and muscle weakness. His serum level of glucose and ketone are abnormally low. He is diagnosed with primary carnitine deficiency. Had there been no carnitine deficiency, how many ATP molecules would have been produced form the complete oxidation of a fatty acid with 14 carbon atoms ?

a) 38

b) 129

c) 92

d) 36

e) 131

 The right answer is- c)- 92 ATPs.

 Fatty acid with 14 carbon atoms will undergo 6 cycles of beta oxidation and yield 7 Acetyl co A.

Number of ATPs per cycle of beta oxidation

1FADH2 = 1.5 ATPs (At the level of Acyl co A dehydrogenase)

1NADH +H+ = 2.5 ATPs (At the level of Beta hydroxy acyl co A dehydrogenase)

Total ATP yield = 4/cycle

In 6 cycles =  6×4 = 24 ATPs

Energy yield per Acetyl co A = 3X2.5 +1.5 = 9 +1(substrate level phosphorylation= 10

Total energy yield through complete oxidation of Acetyl co As=10×7 = 70

Total energy yield = 70 +24 = 94

Net energy yield = 94-2  = 92

(2 ATP used for activation of fatty acids)

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1. A 24-year-old female presents with complaints of intestinal bloating, gas, cramps, and diarrhea following a meal including dairy products. A lactose-tolerance test confirms that she has a deficiency of lactase. Which of the following dairy products could you recommend that would be least likely to cause her difficulties in the future?

a) Condensed milk

b) Cottage cheese

c) Ice cream

d) Skim milk

e) Yogurt

2. A 25 year-old female meets with her family physician. She is interested in starting a family soon and is looking for advice on what nutritional supplements would be beneficial during pregnancy. Which of the two supplements should be considered as the most important?

a) Vitamin K and copper

b) Selenium and thiamine

c) Iron and folate

d) Vitamin C and D

e) Vitamin A and E

3. A 16 -year-old girl presents with severe menstrual camping, caused by increased prostaglandin production. Prostaglandins are synthesized from which of the following?

a) Arachidonic acid

b) Glucose

c) Acetyl co A

d) Palmitic acid

e) Propionyl co A

4. A 45 -year-old man presents with multiple gunshot wounds to the abdomen. He undergoes emergent surgery during which a part of his intestine is resected. After surgery he is placed on total parenteral nutrition (TPN), an intravenous form of nutrition.TPN supplies essential fatty acids also in the diet. Which of the following is an essential fatty acid?

a) Palmitic acid

b) Linoleic acid

c) Elaidic acid

d) Oleic acid

e) Erucic acid

5. A 35 year-old woman presents with severe upper abdominal pain, nausea and vomiting. She is diagnosed with pancreatitis (an inflammation of pancreas). Her serum triglyceride level is 1500 mg/dl (normal 150-199 mg/dl). Triglycerides are primarily synthesized in which of the following tissues?

a) Skeletal muscle

b) Heart muscle

c) Liver

d) Spleen

e) Red blood cells

6. An 8 -year-old boy has been brought to emergency room with generalized tonic/clonic seizure. The child has a history of epilepsy and ataxia. Blood biochemistry reveals lactic acidosis. Upon questioning the parents state that their child was born with the disease, “Pyruvate carboxylase deficiency”. Which of the following products is the fate of pyruvate when the reaction is catalyzed by pyruvate carboxylase?

a) Lactate

b) Alanine

c) Acetyl co A

d) Oxaloacetate

e) Acetaldehyde

7. The catabolism of   1 mol of glucose to lactate in the glycolytic pathway is accompanied by the reduction of how many moles of O2?

a) 0

b) 2

c) 4

d) 8

e) 10

8. After digestion of a piece of cake that contains flour, milk and sucrose as its primary ingredients, the major carbohydrate products entering the blood are-

a) Glucose

b) Galactose and fructose

c) Glucose and galactose

d) Glucose and fructose

e) Fructose, glucose and galactose

9. Which of the following enzymes is not present in muscle?

a) Glycogen synthase

b) Lactate dehydrogenase

c) Glucose-6-Phosphatase

d) Hexokinase        

e) Phosphorylase

10. A 43-year-old man with a long history of poorly controlled hypertension presents to the emergency with a severe headache. His blood pressure is found to be dramatically elevated at 220/150 mm Hg. Which of the following products derived from amino acids, might bring down his highly elevated blood pressure?

a) Melanin

b) Nitric oxide

c) GABA

d) Dopamine

e) Serotonin

 

Answers

 1 – e) – Lactose intolerance is the inability or insufficient ability to digest lactose, a sugar found in milk and milk products. Lactase breaks down lactose into two simpler forms of sugar called glucose and galactose, which are then absorbed into the bloodstream. Lactose intolerance is caused by a deficiency of the enzyme lactase, which is produced by the cells lining the small intestine. Enzyme levels are highest shortly after birth and decline with aging, despite a continued intake of lactose.

Although the body’s ability to produce lactase cannot be changed, the symptoms of lactose intolerance can be managed with dietary changes. Most people with lactose intolerance can tolerate some amount of lactose in their diet. Gradually introducing small amounts of milk or milk products may help some people adapt to them with fewer symptoms. Lactose-free, lactose-reduced milk, Soy milk and other products may be recommended.

The microorganisms that convert milk to yogurt (Streptococcus salivarius thermophilus and Lactobacillus delbrueckii  bulgaricus) metabolize most of the lactose in the milk. Yogurt is also a good source of dietary calcium. Thus yogurt would cause least difficulties and can be safely recommended to the patient.

2- c)- Pregnancy is a time of increased metabolic demand, and two of the most important supplements are Iron and folic acid ;Iron to prevent anemia and folic acid to prevent neural tube defects in the developing fetus. Copper and selenium are the trace elements that are rarely deficient. Thiamine is present in grain products. Vitamin C and D are sufficiently obtained from the diet. Vitamin A derivative are teratogenic and therefore should be avoided during pregnancy. Vitamin K deficiency is common in newborns and often the supplementation is required after birth.

3- a)- Prostaglandins are synthesized from Arachidonic acid; they cannot be synthesized from glucose, acetyl co A, Palmitic acid or propionyl co A.

Arachidonate, which may be obtained from the diet, but is usually derived from the 2nd position of phospholipids in the plasma membrane by the action of phospholipase A2, is the substrate for the synthesis of the prostanoids – prostaglandins (PG2) and thromboxane (TX2) series by the cyclooxygenase pathway, or the leukotrienes- LT4 and Lipoxins -LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate.

4- b)- Linoleic acid is the right answer.  It has 18 carbon atoms and two double bonds (ω6), octadecadienoic acid. Linoleic (ω6), α-Linolenic (ω3) and Arachidonic acid (ω6) are the essential fatty acids. Arachidonic acid is relatively non-essential since it can be synthesized from Linoleic acid in the body.

Palmitic acid is a saturated fatty acid with 18 carbon atoms. Elaidic acid, Oleic acid and Erucic acid are monounsaturated fatty acids (ω9). Elaidic and oleic are Trans and cis isomers respectively with 18 carbon atoms. Elaidic acid is the major Trans fat found in hydrogenated vegetable oils. Erucic acid has 22 carbon atoms and one double bond.

5- c) Liver is the right answer. Triglycerides are mainly synthesized in the liver but they can also be synthesized in the adipose tissue and intestinal cells. In the liver they are packaged in VLDL and are secreted in to the blood. The triglycerides synthesized in the intestine are packaged in chylomicrons and are transported to peripheral cells for utilization. Triglycerides cannot be synthesized in skeletal, heart muscle, spleen and red blood cells. They are stored in adipose tissue and liver.

6- d) The right answer is (d) – Oxalo acetate. Pyruvate carboxylase catalyzes the conversion of pyruvate to oxaloacetate. It is the first step of gluconeogenesis and is also considered an “anaplerotic” or “filling up” or “CO2 fixation reaction” to replenish the oxaloacetate concentration in conditions of sudden influx of Acetyl co A, for the optimum functioning of TCA cycle. Biotin is required as a cofactor in this energy requiring reaction.

Lactate is the product of lactate dehydrogenase catalyzed reaction. Alanine is produced by transamination reaction catalyzed by Alanine transferase (ALT) also called SGPT (Serum glutamate pyruvate transaminase).

Acetyl co A is the product of pyruvate dehydrogenase reaction. Acetaldehyde is the product of pyruvate decarboxylase catalyzed reaction that does not occurs in human beings. This reaction is common in micro organisms and is commercially used for fermentation of glucose for wine production.

7- a) Production of lactate through glycolysis takes place under anaerobic conditions. No oxygen is used; hence the right answer is zero (0). Glycolysis can provide energy in the absence of oxygen; it is the unique pathway that can operate both aerobically as well as anaerobically. One mol of glucose yields 2 moles of lactate, with a yield of 2ATP by substrate level phosphorylation. In aerobic respiration via Electron transport chain O2 is used as a final acceptor and is reduced to water.

8) -e) – As per the ingredients the products would be- Glucose, galactose and fructose.

Flour- Starch-Starch is a polymer of glucose. The digestion of starch would produce glucose.

Milk- Lactose (milk sugar). Lactose is a disaccharide of galactose and glucose. Thus the digestion products of milk would be galactose and glucose.Sucrose is a disaccharide, made up of glucose and fructose. Digestion by sucrase in intestine would produce glucose and fructose.At the end, the net products of digestion entering blood would be – Glucose, galactose and fructose.

9- c) – Glucose-6-phosphatase is not present in muscle and does not contribute to blood glucose. Glucose-6-p produced from gluconeogenesis or from degradation of glycogen is channeled towards glycolytic pathway in muscle. Lactate dehydrogenase is not absent in muscle. In fact excessive lactate accumulation is the reason for muscle fatigue and the lactate produced from pyruvate by the action of lactate dehydrogenase is transported through blood to liver for glucose production (cori’s cycle).Hexokinase is the first enzyme of glycolytic pathway, glycogen synthase is the rate controlling enzyme of glycogenesis synthesis and phosphorylase is the rate limiting enzyme of glycogen degradation, all these three are present in muscle.

10- b) Hypertensive emergencies require immediate lowering of blood pressure. This may be accomplished with IV nitroprusside, a short-acting vasodilator with a rapid onset of action that allows for minute-to-minute control of blood pressure. Nitroprusside acts by releasing Nitric oxide (NO). Nitric oxide was previously referred as endothelial derived relaxing factor. It is a smooth muscle relaxant and a potent vasodilator. Nitroglycerin, amyl nitrite, (isobutyl nitrite or similar) and other nitrite derivatives used in the treatment of heart disease are also  converted to nitric oxide, which in turn dilates the coronary arteries, thereby increasing  the blood supply.

Melanin is derived from Tyrosine and is the major pigment of skin and hair.

GABA (gamma amino butyric acid), a decarboxylation product of glutamic acid is an inhibitory neurotransmitter.

Dopamine is derived from decarboxylation of DOPA, which is a product of tyrosine. Dopamine is used for raising the blood pressure in patients of shock. It is a stimulatory neurotransmitter.

Serotonin is derived from tryptophan; it is also a vasoconstrictor and a stimulatory neuro transmitter. Serotonin is involved in mood elevation and depression.

 

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An 18-year-old college student is brought to the emergency room unconscious, with a very high serum alcohol level. Alcohol metabolism can result in high NADH levels. When NADH enters the electron transport chain, which of the following is the correct order in which electron transfer occurs ?

a) NADH, coenzyme Q, cytochrome c, FMN, O2

b) NADH, cytochrome c, coenzyme Q, FMN,O2

c) NADH, FMN, coenzyme Q, cytochrome c, O2

d) NADH, cytochrome c, FMN, cytochrome c, O2

e) NADH, FMN, cytochrome c, coenzyme Q, O2

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A 56-year-old man with long-standing  poorly controlled diabetes mellitus visits his primary care physician for a follow-up after recent hospitalization. The patient experienced an episode of acute renal failure while in the hospital and his creatinine level rose to 4 mg/dl. Creatinine, a marker of renal function is produced from which of the following precursors ?

a) Glutamine, Aspartic acid and alanine

b) Glutamine, Cysteine and Glycine

c) Serine , Glycine and Methionine

d) Glycine, Arginine and Methionine

e) Glutamic acid, Cysteine and Glycine

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A 56- year- old female presents with difficulty opening her eye lids, as well as inability to raise herself from sitting position. She is diagnosed with “myasthenia gravis”, a disease of extreme fatigue, due to decreased concentration of Acetyl choline in her muscles. She has been prescribed physostigmine, a drug that increases the amount of available Acetyl choline, by competitively inhibiting acetylcholinestrase.

myashenia gravis

Figure- Inability to open eyelid in myasthenia gravis

Which of the following statements is not true of competitive inhibitors ?

a) Vmax remains the same

b) Apparent  Km in increased

c) Inhibitor is a structural analogue of the substrate

d) Inhibitor binds covalently to the enzyme

e) Increasing concentration of substrate can reverse the changes

 3- A 55-year-old male presents with difficult breathing and swollen ankles. He is found to have a failing heart, resulting in blood backing up in to his lungs (pulmonary congestion) and making it difficult for him to breathe. He is administered a drug  that inhibits angiotensin converting enzyme (ACE). By inhibiting this enzyme, which of the following will change about the reaction it catalyzes ?

a) Energy of activation

b) Net free energy change

c) Equilibrium concentration of substrate

d) Equilibrium concentration of product

e) Thermodynamics

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Refer to the following graphs and answer the question

 Enzyme inhibitio1

 

 

 

 

 

 

 

 

 

 

 

Enzyme inhibition-2

 

 

 

 

 

 

 

 

 

 

 

 

 

A 20 year- old man was brought to the emergency with vomiting, sweating, drooling and a decreased heart rate. History reveals that he was in a corn field when it was sprayed by a crop duster. The pesticide causing his symptoms is an organo phosphate that covalently binds to acetyl cholinesterase and inactivates the enzyme. The enzyme kinetics affected by the inhibitor are shown in the figures. What is the mechanism of inhibition of this enzyme ?

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