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CLINICAL QUESTIONS

81. Oral contraceptives are known to lower blood levels of folate and vitamin B6. Which of the
following conversion processes might be directly affected?
A.
Ornithine to Citrulline
B.
Histidine to histamine
C.
Glutamate to Glutamine
D.
Propionyl co A to Methyl malonyl co A
E.
Phenyl alanine to Tyrosine
Answer- B- The correct answer is conversion of Histidine to histamine. The reaction is
catalyzed by decarboxylase that requires B6-P as a cofactor (Figure-1) that gets deficient in
women upon long-term oral contraceptive usage. Folic acid is not required in this reaction.

Figure-1- Decarboxylation of Histidine is carried out by histidine decarboxylase. Histamine is


an important chemical for allergies and anaphylaxis. PLP is pyridoxal phosphate(B6-P)
The conversion of Ornithine to citrulline (Figure-2) takes place in urea formation. None of these
vitamin B6 or folic acid is required in this conversion process.

Figure-2- Ornithine to citrulline conversion is carried out by ornithine transcarbamoylase,


which is an important mitochondrial enzyme required for urea synthesis.
Glutamate to glutamine conversion is catalyzed by glutamine synthetase (figure-3). It is a
reaction to detoxify ammonia, the first line of defense in brain. These vitamins are not required
in this reaction process.

Figure-3- Gammaglutamyl phosphate is an intermediate in the conversion of Glutamate to


glutamine, Propionyl coA to Methylmalonyl coA conversion requires biotin as a coenzyme
(figure-4). It is a carboxylation reaction; ATP is also required for this process.

Figure-4- Propionyl coA to methylmalonyl coA conversion is an intermediate step in the actual
conversion of propionyl coA to Succinyl coA, which is an intermediate of TCA cycle.
Phenylalanine to Tyrosine conversion requires Tetrahydrobiopterin (BH4) as a coenzyme. The
reaction is catalyzed by Phenylalanine hydroxylase and it is the first step of metabolism of
phenylalanine (figure-5)

Figure-5- Phenylalanine hydroxylase catalyzing the conversion of phenylalanine to tyrosine is a


monooxygenase, deficiency of which causes Phenylketonuria.

82. During a medical rotation, a medical student volunteered for a respiratory physiology exam
that determines basal metabolic rate and the respiratory quotient. She followed the protocol
for a resting individual in the post absorptive state. Which of the following amino acids
would be found in the highest concentration in serum?
A.
B.
C.
D.
E.

Alanine and Glutamine


Arginine and Ornithine
Glutamate and Aspartate
Branched chain amino acids
Hydrophobic amino acids

Answer- A- Alanine and Glutamine.


Post absorptive state is the state of the body 3-5 hours after meals.
It is that period of time in the body during which cell metabolism is primarily fueled by
nutrients stored from previous meals; this state is dominated by glucagon release from the alpha
cells of the pancreatic islets in response to hypoglycemia; various insulin antagonists, thyroid
hormones (T3 and T4), glucocorticoids (cortisone, cortisol, hydrocortisone) from the adrenal
cortex, epinephrine from the adrenal medulla, and human growth hormone from the anterior
pituitary are also present in increased amounts and and contribute to the physiological processes
which occur in this state.
Primarily, hepatocytes are the responsive targets to glucagon and, in response to glucagon
arrival, release glucose into the plasma to be used by nervous tissue in oxidative pathways to
generate ATP.
The liver obtains this glucose in two ways:
(1)

by releasing glucose which had been stored as glycogen (glycogenolysis) and

(2) by synthesizing new glucose molecules from the breakdown products of lipid and protein
catabolism (gluconeogenesis)
Most other tissues shift to energy production from lipid and protein catabolism. Adipocytes
liberate fats (triglycerides) into the bloodstream (lipolysis) to support the metabolism of these
other tissues, the glycerol released from triglycerides is used to synthesize glucose
(gluconeogenesis); the liver oxidizes free fatty acids for fuel, producing ketone bodies
(ketogenesis) as by-products (figure)
Nervous tissue is not responsive to glucagon, but continues to utilize the glucose.

Figure- Changes occurring in the post absorptive state


In the post absorptive state, the muscles release alanine and glutamine which are found in
highest concentration. Most of the alanine is removed by liver (glucose- alanine cycle) and
glutamine is taken up by kidney. The carbon skeleton of alanine is used for glucose production
whereas amino group is removed in the form of ammonia which is detoxified forming urea.
In the kidney glutamine is hydrolyzed by glutaminase enzyme forming ammonia and glutamate.
Ammonia is converted to ammonium ion and contributes to acid secretion by the kidney. Renal
glutaminase activity is increased in conditions of acidosis to promote acid secretion whereas in
conditions of alkalosis the glutaminase activity is decreased to enhance acid retention in the
body.
The other set of amino acids are not increased in serum more than alanine and glutamine in the
post absorptive state. Since the amino acids are not available at that time through diet in the post
absorptive and the body cannot synthesize them, the essential amino acids such as branched
chain amino acids or arginine cannot be in higher concentration. Aspartate and glutamate are
mainly used for transamination reactions, mediating transfer of amino group from one amino
acid to another, so they are never in high concentration in serum themselves under physiological
conditions.
Thus the only option is A- Alanine and Glutamine.

83. A new-born becomes progressively lethargic after feeding. His respiratory rate increases and
he becomes virtually comatose, responding only to painful stimuli, and exhibits mild
respiratory alkalosis. Suspicion of a urea cycle disorder is aroused and evaluation of serum
amino acid levels is initiated. In the presence of hyperammonemia, production of which of
the following amino acids is always increased?
A.
B.
C.
D.
E.

Glycine
Arginine
Proline
Histidine
Glutamine

Answer- The correct answer is Glutamine. Urea cycle disorder results in reduced ammonia
disposal and hence the patients present with symptoms of hyperammonemia.
Ammonia is detoxified by coupling with Glutamate to form Glutamine. This is the first line of
defense. The reaction is catalyzed by Glutamine synthetase (figure-1).

Figure-1- Conversion of glutamate to glutamine


In conditions of hyperammonemia, Glutamate becomes limiting and its concentration is
compensated by Amination of alpha-ketoglutarate (a TCA cycle intermediate) to form
Glutamate. The reaction is catalyzed by glutamate dehydrogenase (Figure-2). Glutamate can be
subsequently aminated with another ammonia molecule to form Glutamine. Thus glutamine
concentration increases in blood during conditions of hyperammonemia.

Figure-2- Showing conversion of glutamate to Alpha ketoglutarate.

The reversible reaction is catalyzed by glutamate dehydrogenase. The direction of the reaction
depends upon the levels of NADH/NADPH. In normal health the forward reaction is favored,
while in hyperammonemia the reaction proceeds towards formation of glutamate.
Ammonia intoxication
Excess of ammonia depletes glutamate and hence GABA level in brain, since Glutamate upon
decarboxylation produces GABA (Figure-3). To compensate for glutamate, alpha ketoglutarate
is used, the decreased concentration of which subsequently depresses TCA and thus deprives
brain cells of energy. Excess Glutamine is exchanged with Tryptophan, a precursor of
Serotonin, resulting in hyper excitation. The symptoms of ammonia intoxication are all due to
energy depletion and a state of hyper excitation.
Figure-3- Formation of GABA from glutamate.
As regards other options - Glycine, histidine and proline have no roles in detoxification of
ammonia and hence the concentrations of these amino acids remains unaffected.
Arginine level can increase depending upon the level of blockage in the urea cycle.

84. A 55-year-old man suffers from cirrhosis of liver. Toxins such as ammonia are not properly
metabolized by the liver in this disease and can damage the organs such as brain. Which of
the following amino acids covalently binds ammonia, transports and stores it in a non toxic
form?
A.
B.
C.
D.
E.

Tryptophan
Alanine
Aspartate
Glutamate
Glutamine

The correct answer is- D-Glutamate.


Glutamate occupies a central place in the amino acid metabolism. Basically it acts as a collector
of amino group of the amino acids. Free ammonia is toxic to the body especially to brain cells;
it is transported in the bound form to liver where it is finally detoxified forming urea.
The first line of defense from ammonia intoxication is conversion of glutamate to Glutamine.
Excess of ammonia depletes glutamate and hence GABA level in brain, to compensate for

glutamate, alpha keto glutarate is used, the decrease concentration of which subsequently
depresses TCA and thus deprives brain cells of energy. Excess Glutamine is exchanged with
Tryptophan, a precursor of Serotonin, resulting in hyper excitation. The symptoms of ammonia
intoxication are all due to energy depletion and a state of hyper excitation.
As regards other options, Tryptophan has no role in the transport of ammonia. Alanine is a
transporter of ammonia from muscle- Glucose Alanine cycle. Aspartate is required for
transamination reactions and glutamine is produced from glutamate by coupling with ammonia.
85. A 45-year-old female presents to her primary care doctor with fatigue and
tingling/numbness in her extremities (bilateral). Examination reveals a beefy red and
fissured tongue. Further evaluation reveals a low Glutathione reductase activity in the red
blood cells. Which of the following vitamin deficiencies could have caused her symptoms?
A.
B.
C.
D.
E.

Vitamin C
Niacin
Vitamin B2
B6-P
Vitamin B12

The correct option is C- vitamin B2.


The patient is most probably suffering from Vitamin B2 deficiency (Riboflavin deficiency).
Most prominent effects of vitamin B2 deficiency are seen on the skin, mucosa and eyes. The
characteristic symptoms are: Glossitis (magenta tongue, geographical tongue), cheilosis,
angular stomatitis (fissures at the corners of the mouth), sore throat, burning of the lips, mouth,
and tongue, inflammed mucous membranes, seborrheic dermatitis (moist scaly skin
inflammation), and corneal vascularization associated with sensitivity to bright light and
impaired vision.
Riboflavin deficiency rarely occurs in isolation, mostly it is found in association with
deficiencies of other B-complex vitamins. It is frequent in chronic alcoholics. It can also occur
in patients with chronic liver diseases, and in hospitalized patients who receive total parenteral
nutrition (TPN) with inadequate riboflavin supplementation.
Riboflavin is essential for healthy skin, nails, hair growth and general good health, including
regulating thyroid activity. Riboflavin supports energy production by aiding in the metabolism
of fats, carbohydrates, and proteins.
In the body, riboflavin occurs primarily as an integral component of the coenzymes Flavin
mononucleotide (FMN) and Flavin adenine dinucleotide (FAD). These coenzymes participate in
a large majority of the reactions in the body.

Enzymes that contain Flavin adenine dinucleotide (FAD) or Flavin-mononucleotide (FMN) as


prosthetic groups are known as Flavoenzymes.
Flavoproteins play very important roles in the electron transport chain Decarboxylation of
pyruvate and -Ketoglutarate requires FAD besides other coenzymes.
FAD is required as a coenzyme for, monoamine oxidase and glutathione reductase.
Fatty acyl CoA dehydrogenase requires FAD in fatty acid oxidation
86. A 45-year-old obese male presents for a routine examination. He has a sedentary life style
and eats a high-fat diet. His triglyceride level is abnormally elevated. When glycerol derived
from adipose triglycerides is converted to glucose, how many moles of high- energy
phosphates are required?
A.
B.
C.
D.
E.

1
2
3
4
6

Answer- The correct answer is B- 2 ATP.


Glycerol is phosphorylated at the expense of ATP to form Glycerol-3-P; the reaction is
catalyzed by glycerol Kinase. Glycerol-3-P enters the main pathway of Gluconeogenesis at the
level of Dihydroxy acetone-P (Figure-1). Since glycerol is a three carbon compound, hence two
glycerol and two ATP molecules (one ATP per glycerol) are required for their conversion to
glucose.

Figure-1- Glycerol -3-P the product of glycerol kinase reaction is converted to Dihydroxy
acetone-P before its entry in to the main pathway of gluconeogenesis.
The overall reaction of gluconeogenesis is-

Six nucleotide triphosphate molecules are hydrolyzed to synthesize glucose from pyruvate in
gluconeogenesis (Figure-2)
But in case of Glycerol only 2 ATP are hydrolyzed to synthesize glucose. DHAP (Dihydroxy
acetone-P) condenses with glyceraldehyde-3-P forming fructose 1, 6 bisphosphate and there is
no energy expenditure onwards (Figure-2).

Figure2- showing reactions and energetics of gluconeogenesis.

87. Lactate is oxidized to pyruvate in a reaction catalyzed by Lactate dehydrogenase. The


patients with genetic deficiency of lactate dehydrogenase present with muscle cramping and
myoglobinuria after intense exercise. The sources of lactate include muscle and red blood
cells. Lactate is a waste product in such cells; it is transported to liver and can be converted to
glucose through pathway of gluconeogenesis. The energy requirements for conversion of
lactate to glucose are:
A.
B.
C.
D.
E.

2 ATP
4 ATP
6 ATP
8 ATP
38 ATP

The correct answer is C- 6 ATP.


Lactate produced by active skeletal muscle and erythrocytes is a source of energy for other
organs. Erythrocytes lack mitochondria and can never oxidize glucose completely. In
contracting skeletal muscle during vigorous exercise, the rate at which glycolysis produces
pyruvate exceeds the rate at which the citric acid cycle oxidizes it. The rate of formation of
NADH by glycolysis is also greater than the rate of its oxidation by aerobic metabolism.
The accumulation of both NADH and pyruvate is reversed by lactate dehydrogenase, which
oxidizes NADH to NAD+ as it reduces pyruvate to lactate (Figure-1)

Figure-1- Pyruvate and lactate are inter-convertible, the net amount depends upon the ratio of
NADH/NAD+. In conditions of NAD+ excess, (as in the liver) pyruvate is the end product,
whereas under anaerobic conditions or in the cells lacking mitochondria, lactate is the important
product of this reaction.
This reaction serves two critical functions during anaerobic glycolysis.
1) Regeneration of NAD+ In the direction of lactate formation, the LDH reaction requires
NADH and yields NAD+ which is then available for use by the glyceraldehyde-3-phosphate
dehydrogenase reaction of glycolysis. These two reactions are, therefore, intimately coupled
during anaerobic glycolysis (figure-2).

Figure-2- Coupling of reactions for the continuation of glycolysis. The purpose of the reduction
of pyruvate to lactate is to regenerate NAD+ so that glycolysis can proceed in active skeletal
muscle and erythrocytes.
2) Gluconeogenesis- The lactate produced by the LDH reaction is at a dead-end in metabolism.
It must be converted back, therefore it is released to the blood stream and transported to the
liver where it is oxidized to pyruvate, through the same reaction catalyzed by lactate
dehydrogenase favored by the low NADH/NAD+ ratio in the cytosol of liver cells. Pyruvate in
the liver is converted into glucose by the gluconeogenic pathway. Glucose then enters the blood
and is taken up by skeletal muscle. Thus, the liver furnishes glucose to contracting skeletal
muscle, which derives ATP from the glycolytic conversion of glucose into lactate. Contracting
skeletal muscle supplies lactate to the liver, which uses it to synthesize glucose. These reactions
constitute the Cori cycle (figure-3). The formation of lactate buys time and shifts part of the
metabolic burden from muscle to other organs.

Figure-3- Cori cycle- Glucose is transported to skeletal muscle, for energy needs.
The product of glycolysis, lactate cannot be converted back to pyruvate due to high
NADH/NAD+ ratio, lactate is transported back to liver for reconversion to pyruvate and then to
glucose through the pathway of gluconeogenesis. Glucose is again transported to muscle for
usage and this cycle continues for waste disposal and making the best use of the waste product.

An overview of gluconeogenesis
The three irreversible reactions of glycolysis are substituted by 4 alternative reactions1)
First barrier- Pyruvate cant be converted directly to phosphoenol pyruvate due to
irreversible reaction catalyzed by pyruvate kinase. To overcome this barrier, alternatively
pyruvate is first converted to oxaloacetate and then oxaloacetate is converted to Phospho enol
pyruvate by two separate reactions (figure-4).
2) Second barrier- From phosphoenol pyruvate onwards up to fructose 1,6 bisphosphate, the
reactions are reversible, the second barrier lies at the level of conversion of fructose 1,6,
bisphosphate to fructose 6, phosphate, which is overcome by fructose 1,6 bisphosphatase
(figure-4).
3) Third barrier- The conversion of glucose-6-P to free glucose (third barrier) is carried out by
glucose-6-phosphatase (figure-4), which is the third and the final barrier of gluconeogenesis.

Figure-4- An overview of gluconeogenesis, highlighting the energy requiring steps.

88. A 22- year-old diabetic comes to the Accident and Emergency department. She gives a 2day history of vomiting and abdominal pain. She is drowsy and her breathing is deep and
rapid. There is distinctive smell from her breath. She has been diagnosed with Diabetic
ketoacidosis. Diabetic ketoacidosis is a complication of uncontrolled diabetes mellitus. The
TCA cycle in diabetes mellitus is suppressed and the excess Acetyl coA, resulting from fatty
acid oxidation is channeled towards the pathway of ketogenesis.
Which of the following intermediates of TCA cycle is depleted in Type 1 Diabetes mellitus to
suppress TCA cycle?
A.
B.
C.
D.
E.

Succinate
Malate
-Keto glutarate
Oxaloacetate
Pyruvate.

The correct answer is- D) Oxaloacetate.


Two facts demand attention here1)

TCA cycle suppression and

2)

Basis of ketogenesis

In Diabetes mellitus, TCA cycle is in a state of suppression due to diminished availability of


oxaloacetate which is channeled towards the pathway of gluconeogenesis.
The hyperglycemia in Insulin deficiency results from decreased utilization and excess pouring
in of glucose. The processes of glucose utilization such as- Glycolysis, TCA cycle, HMP and
glycogenesis occur at a diminished rate, whereas rates of gluconeogenesis and glycogen
degradation are increased due to disturbed Insulin to Glucagon ratio in diabetes mellitus.
Oxaloacetate is a common intermediate of TCA cycle and gluconeogenesis. The utilization of
oxaloacetate in the pathway of gluconeogenesis depletes the amount which is required for TCA
cycle (Oxaloacetate acts as a catalyst; an optimum amount of oxaloacetate is required for the
functioning of TCA cycle), therefore it undergoes in a state of suppression.
As glucose utilization is decreased in Diabetes mellitus, alternatively fatty acids are oxidized to
compensate for the energy needs. Excess fatty acid oxidation results in:
i) Accumulation of NADH which further suppresses TCA cycle (Excess of NADH decreases the
catalytic activities of three NAD+ requiring enzymes of TCA cycle-Isocitrate dehydrogenase,
Alpha ketoglutarate dehydrogenase and Malate dehydrogenase), and

Figure-1- Regulation of TCA cycle.


The accumulation of NADH inhibits the activities of NAD+ enzymes of TCA cycle, isocitrate
dehydrogenase, Alpha keto glutarate dehydrogenase and Malate dehydrogenase. The activity of
PDH complex is also decreased.
ii) Accumulation of Acetyl co A- The end product of fatty acid oxidation cannot be oxidized in
TCA cycle at the same rate as that of its production, as a result, Acetyl coA is channeled either
towards pathways of ketogenesis, or of cholesterol synthesis (figure-2).

Figure-2- a) The rate of lipolysis is increased; fatty acids are oxidized to produce Acetyl CoA.
b) Due to non-availability of oxaloacetate, which is diverted towards pathway of
gluconeogenesis, TCA cycle is suppressed.

c) Acetyl co A is diverted towards pathway of ketogenesis. Acetone, acetoacetate and beta


hydroxy butyrate are the three ketone bodies
d) Accumulated ketone bodies, (being acidic in nature and also as they deplete the alkali
reserve) cause acidosis.
In Type 1 Diabetes mellitus, the onset of the disease is abrupt, which is why the body switches
abruptly from glucose utilization to fatty acid oxidation for energy needs. Acetyl coA resulting
from excess fatty acid oxidation saturates TCA cycle and the other alternative pathways
resulting in ketogenesis. This is the reason ketoacidosis is far more commonly found in type
1diabetes mellitus than type 2 diabetes.
The similar situation is observed in prolonged fasting or starvation. Diabetes mellitus and
starvation depict a similar metabolic state, in both the conditions, the cells are deprived of
glucose and switch to alternative fuels for their energy needs. The basis of ketosis is thus the
same in both conditions.
As regards other options:
A) Succinate-Succinate is an intermediate of TCA cycle, but it is not depleted in Diabetes
mellitus.
B) Malate- Similarly malate and C) -Ketoglutarate are also not depleted in Diabetes mellitus.
E) Pyruvate depletion does not directly affect the functioning of TCA cycle, of course pyruvate
is also diverted towards glucose production, but there are other sources available, in any case
TCA cycle activity is not affected.
Thus the most logical option is Oxaloacetate which is the most important regulator of TCA
cycle, depletion of which suppresses TCA cycle.
89. A 50-year-old, alcoholic male presents with a swollen face, distended abdomen, and an
enlarged fatty liver. Fatty acids react with glycerol-3-P to form triglycerides, which
accumulate to cause fatty liver. The liver has glycerol kinase, while adipose tissue lacks
glycerol kinase. As a result, in adipose tissue, which of the following occurs?
A.
B.
C.
D.
E.

Glucose cannot be converted to DHAP (dihydroxyacetone phosphate)


Glycerol cannot be converted to Glycerol-3-P
DHAP cannot be converted to Glycerol-3-P
Diacylglycerol cannot be converted to Triacylglycerol
Triacylglycerols cannot be stored.

The correct answer is- B) Glycerol cannot be converted to Glycerol-3-P.


Glycerol kinase catalyzes the phosphorylation of glycerol to glycerol-3-p. Glycerol released
through adipolysis (breakdown of triglycerides) cannot be reutilized, as it has to be in the

phosphorylated form, and glycerol kinase deficiency in adipose tissue makes glycerol a waste
product (figure).
Therefore, Glycerol is transported to liver, where upon conversion to dihydroxy acetone
phosphate, (figure), it is either converted to glucose (through pathway of gluconeogenesis), or is
completely oxidized through glycolytic pathway. The fate of glycerol is decided by the cellular
requirements.
1) In the fasting state- Glycerol released from lipolysis of adipose tissue triacylglycerol is used
solely as a substrate for gluconeogenesis in the liver and kidneys. The conversion of glycerol to
glucose requires phosphorylation to glycerol-3-phosphate by glycerol kinase and
dehydrogenation to Dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate
dehydrogenase (G3PDH) (Figure). The G3PDH reaction is the same as that used in the transport
of cytosolic reducing equivalents into the mitochondrion for use in oxidative phosphorylation.
This transport pathway is called the glycerol-phosphate shuttle.

Figure-Glucose-Glycerol cycle. Glycerol released from adipocyte is used in the liver either for
energy production or is utilized as a substrate for gluconeogenesis. Glycerol is initially
converted to glycerol-3-P, in a reaction catalyzed by glycerol kinase. Subsequently glycerol-3-P
is converted to Dihydroxy acetone-P (DHAP) by glycerol-3-p dehydrogenase. It is a reversible
reaction. DHAP can then enter the pathway of glucose production. Glucose produced is
transported back to adipocyte to complete the cycle. The entry of glucose in the adipocyte is by
GLUT4 receptors that are regulated by Insulin.
2) In the well fed state- Glycerol upon conversion to DHAP in liver (as described above), is
oxidized completely through the pathway of glycolysis. Glycolytic pathway is involved both for
the utilization and production of glycerol-3-P.
It is noteworthy that glycerol-3-P in adipose tissue is obtained through glycolytic pathway
(figure), and not by direct phosphorylation of glycerol (glycerol kinase is absent in adipose
tissue). In fact adipocytes require a basal level of glycolysis in order to provide them with
DHAP as an intermediate in the synthesis of triacylglycerols.
As regards other options:

A) Glucose cannot be converted to DHAP (dihydroxy acetone phosphate) This in incorrect,


Glucose can be converted to DHAP through glycolytic pathway (figure).
C) DHAP cannot be converted to Glycerol-3-P- This is also incorrect, DHAP is converted to
Glycerol-3-P, in a reaction catalyzed by Glycerol-3-P dehydrogenase.
D) Diacylglycerol cannot be converted to Triacylglycerol- Diacyl glycerol can be converted to
triacylglycerol. This is also not a correct option.
E) Triacylglycerols cannot be Stored-Incorrect again, Triacylglycerols can be stored in an
unlimited amount in the adipose cells.
Thus the most appropriate option is B) Glycerol cannot be converted to Glycerol-3-P due to
deficiency of glycerol kinase.
90. A newborn infant presents with poor feeding, vomiting, jaundice and an enlarged liver. The
urine test is positive for a reducing substance. Which of the following conversions is most
likely to be normal?
A.
B.
C.
D.
E.

Glucose to Galactose
Activated galactose to activated Glucose
Lactose to galactose
Excretion of galactose by kidney
Excretion of glucose by kidney

Answer- The correct answer is- B-Conversion of activated galactose to activate glucose.
As evident from the clinical features, the child is suffering from Galactosemia.
Galactosemia is associated with the following 3 enzyme deficiencies;
1) Classical galactosemia is a major symptom of three enzyme defects. It results from loss
of the enzyme galactose-1-phosphate uridyl transferase.
2) The second form of galactosemia results from a loss of Galactokinase and
3) The third disorder results from a deficiency of UDP-galactose-4-epimerase (Figure)
Galactokinase

Figure- Metabolism of galactose


Galactose-1-phosphate uridylTransferase (GALT) deficiency is the most common enzyme
deficiency that causes Galactosemia.
Galactose-1-phosphate uridylTransferase (GALT) catalyzes conversion of galactose-1-p to UDP
Galactose (Figure-1). This is an important reaction during the metabolism of galactose.
Galactokinase catalyzes the conversion of galactose to galactose-1-P; its deficiency is less
common and is less severe.
UDP galactose epimerase catalyzes the interconversion of UDP galactose to UDP glucose.
Thus except for Galactokinase, the other two enzymes catalyze the interconversion of activated
galactose and activated glucose.
As regards other options:
As such the conversion of glucose to galactose is not possible. They can be interconverted only
in the activated forms
Lactose to galactose conversion takes place by lactase enzyme which is deficient in lactose
intolerance. Lactose intolerance does not produce the symptoms as described above.
Excretion of galactose or glucose by kidney can get impaired only in renal failure; enzymes are
not involved in their excretion from the kidney.
Hence considering the diagnosis of galactosemia in this child, the most suitable option is- B,
impairment of conversion of activated galactose to activated glucose.

91. A 7-month-old baby girl, the second child born to unrelated parents was brought to
Pediatrics outdoor department. History revealed that she did not respond well to breastfeeding and was changed entirely to a formula based on cows milk at 4 weeks. Between 7
and 12 weeks of age, she was admitted to the hospital twice with a history of screaming after
feeding, but was discharged after observation without a specific diagnosis. Elimination of
cows milk from her diet did not relieve her symptoms; her mother reported that the
screaming bouts were worse after the child drank juice and that she frequently had gas and a
distended abdomen. The child was diagnosed having Hereditary fructose intolerance. The
mother of the child was instructed to eliminate fructose containing foods from the childs diet
and was strictly instructed to feed milk without table sugar. The table sugar (sucrose), a
disaccharide, contains glucose and fructose linked as:
A.
B.
C.
D.
E.

O--D-glucopyranosyl-(1->6)- -D-fructofuranoside
O--D-glucopyranosyl-(1->6)- -D-fructofuranoside
O--D-glucopyranosyl-(1->2)- -D-fructofuranoside
O--D-glucopyranosyl-(1->2)- -D-fructofuranoside
None of the above

The correct answer is C- O- D-glucopyranosyl-(1->2)- -D-fructofuranoside.


The onset of symptoms after ingestion of juice (fructose or fructose containing diet) is a sign of
hereditary fructose Intolerance.
Hereditary fructose intolerance is caused by deficiency of Aldolase B, the enzyme required for
the metabolism of fructose. These patients are healthy and asymptomatic until fructose or
sucrose (table sugar) is ingested (usually from fruit, sweetened cereal, or sucrose-containing
formula). Elimination of dietary fructose is both a compulsory and therapeutic step.
In patients who are ill, elimination may also serve as a diagnostic test because all symptoms
should completely resolve. With this treatment, as the patient matures, symptoms become
milder, even after fructose ingestion, and the long-term prognosis is good.
Table sugar (sucrose) is a source of fructose and in Sucrose, the anomeric carbon atoms of a
glucose unit and a fructose unit are joined; the configuration of this glycosidic linkage is -for
glucose and -for fructose (figure).

Figure- Structure of sucrose


Sucrose can be cleaved into its component monosaccharides by the enzyme sucrase.

A.
B.
C.
D.
E.

An overview of properties of sucrose:


Sucrose has no free reactive group because the anomeric carbons of both
monosaccharides units are involved in the glycosidic bond. Therefore, sucrose neither
shows reducing nor mutarotation characters.
Sucrose is called invert sugar because the optical activity of sucrose (dextrorotatory) is
inverted after hydrolysis (by an acid or an enzyme (invertase or sucrase) into an
equimolar mixture of its two components glucose (+52.5) and fructose (-92.5) and the
optical activity of the mixture becomes levorotatory.
92. A 58-year-old man with a history of heavy drinking presents with confusion, unstable gait,
and nystagmus. A provisional diagnosis of Wernickes- Korsakoff syndrome is made. Which
of the patients enzymes of the pentose phosphate pathway is inhibited due to vitamin
deficiency in this case?
Transaldolase
Transketolase
Glucose-6-P- dehydrogenase
Epimerase
Phosphogluconate dehydrogenase
The correct answer is B. Transketolase.
Wernicke-Korsakoff syndrome (thiamine deficiency) is often associated with chronic
alcoholics. Thiamine deficiency is uncommon except in alcoholics as a result of nutritional
deficiencies and malabsorption. The term Wernickes encephalopathy is used to describe the
clinical triad of confusion, ataxia, and nystagmus (or ophthalmoplegia). When persistent
learning and memory deficits are present, the symptom complex is often called WernickeKorsakoff syndrome. Clinically, this term is best conceptualized as 2 distinct syndromes with
acute/subacute confusional state and often reversible findings of Wernickes encephalopathy
versus persistent and irreversible findings of Korsakoff dementia.
Heavy, long-term alcohol use is most commonly associated with Wernicke-Korsakoff
syndrome. Within 2-3 weeks of decreased intake and thiamine depletion, areas of the brain with
the highest thiamine content and turnover will demonstrate cellular impairment and injury.
A deficiency in thiamine will decrease the efficiency of the enzymes for which TPP is required
as a cofactor namely, PDH complex, alpha ketoglutarate dehydrogenase complex, Alpha
ketoacid dehydrogenase complex and the activity of Tryptophan pyrrolase.
A deficiency in thiamine also adversely affects the flux of glucose metabolized by the pentose
phosphate pathway. Transketolase activity requires the cofactor TPP to transfer the
glycoaldehyde unit from a ketose to an aldose in the remodeling reactions of the pathway. When
these reactions cannot proceed, precursor metabolites build up, and the flow through the
pathway is decreased. This results in a decreased production of NADPH and decreased

conversion of glucose to pentose, including ribose. This can lead to decreased regeneration of
reduced glutathione and susceptibility to oxidative stress.
Transketolase is the only TPP (Thiamine pyrophosphate) dependent enzyme in the list. The
reaction catalyzed by Transketolase is shown in the figure

Figure- Reaction catalyzed by Transketolase.


TPP is required as a coenzyme for this reaction.
93. An 18-year-old female is diagnosed as obese. She maintains a sedentary life style and eats a
high-fat, high-sugar diet. Maintenance of this diet and lifestyle has led to lipogenesis and
obesity. Which of the following best explains carbohydrates induced obesity?
A.
B.
C.
D.
E.

Excess glycerol is obtained through glycolysis


Fatty acids are excessively synthesized from Acetyl co A
NADPH is excessively obtained through HMP pathway
Triglycerides are excessively synthesized
All of the above.

The correct answer is E- All of the above. Excess carbohydrate ingestion is a major cause of
obesity. Obesity is a state of excess adipose tissue mass. Adipose tissue is composed of the
lipid-storing adipose cell and a stromal/vascular compartment in which cells including
preadipocytes and macrophages reside. Adipose mass increases by enlargement of adipose cells
through lipid deposition, as well as by an increase in the number of adipocytes. The
predominant lipid in the adipose cells is triglyceride. Triglyceride contains a glycerol backbone
and three fatty acids.
Carbohydrates increase the triglyceride load by the following mechanisms:
Glucose is the principal representative of carbohydrates. The metabolism of glucose provides all
the substances required for the synthesis of triglycerides, for example,
a) Glycerol- Glycerol is obtained through glycolysis (figure-1). Dihydroxyacetone-P
(produced by the cleavage of Fructose 1, 6 bisphosphate) is converted to glycerol-3-P by
the action of Glycerol-3-P dehydrogenase. Glycerol-3-P or active glycerol is used for the
synthesis of Triglyceride (figure-1).

b) Fatty acids- Acetyl co A, the precursor of fatty acids is obtained from Pyruvate, the end
product of glycolysis (Acetyl co A can also be obtained through alternative sources).
c) NADPH- HMP pathway, the alternative pathway of glucose utilization provides NADPH,
for this reductive pathway of fatty acid biosynthesis.
d) Role of insulin- Insulin released as a result of excess plasma glucose load, activates
Acetyl co A carboxylase, the rate limiting enzyme of fatty acid biosynthesis. Insulin also
promotes glucose uptake through GLUT-4 receptors, and hence provides precursors for
fatty acid synthesis and activates Lipoprotein lipase, providing more fatty acids, obtained
through degradation of lipoproteins for esterification with glycerol.

Figure-1- Summary of glucose induced obesity


Excess fructose and sucrose intake is also responsible for increased triglyceride levels and
obesity. Fructose undergoes more rapid glycolysis in the liver than does glucose, because it
bypasses the regulatory step catalyzed by phosphofructokinase (Figure-2). This allows fructose
to flood the pathways in the liver. High fructose consumption can lead to excess pyruvate
production, causing a buildup of Krebs cycle intermediates. Accumulated citrate can be
transported from the mitochondria into the cytosol of hepatocytes, converted to acetyl CoA by
citrate lyase and directed toward fatty acid synthesis. Additionally, DHAP can be converted to
glycerol 3-phosphate as previously mentioned, providing the glycerol backbone for the
triglyceride molecule. Triglycerides are incorporated into very low density lipoproteins
(VLDL), which are released from the liver destined toward peripheral tissues for storage in both
fat and muscle cells.

Figure-2- Summary of carbohydrate induced obesity.


Since all the above mentioned mechanisms are involved in lipogenesis, induced by excess
carbohydrates intake, thus E- is the correct option.
94. A teenager finishes eating a hot fudge sundae and a milk shake. As her blood sugar rises, the
liver recruits both Glucokinase (km = 10.0m M) and Hexokinase (km = 0.10mM) to
metabolize the glucose. Which of the following is a correct statement about the kinetics of
these two enzymes?
A.
B.
C.
D.

Hexokinase will metabolize 100 times more glucose molecules


Hexokinase will lower the energy of activation more than glucokinase
Hexokinase has a much higher affinity to glucose than glucokinase
Hexokinase will have a higher Vmax than glucokinase

E.

Hexokinase will be induced more than glucokinase by the rising concentration of


glucose

Hexokinase has a much higher affinity for glucose than Glucokinase. It is not about number
of Glucose molecules metabolized, or about energy of activation. Km signifies the affinity of
the enzyme for its substrate.
95. During an extended period of exercise, the enzymes involved in the glycolytic pathway
in muscle tissue are actively breaking down glucose to provide the muscle energy. The
liver, to maintain blood glucose levels, is synthesizing glucose via the gluconeogenic
pathway.
Which of the following enzymes involved in these pathways would be most likely to
exhibit MichaelisMenten kinetics, that is, have a hyperbolic curve when plotting
substrate concentration versus velocity of the reaction?
A. Fructose-1, 6-bisphosphatase
B. Hexokinase

C. Lactate dehydrogenase
D. Phosphofructokinase-1
E. Pyruvate kinase
The correct option is C- Lactate dehydrogenase. All the above mentioned enzymes are allosteric
except Lactate dehydrogenase.
96. A 23 year- old female was brought for consultation by her mother who was troubled by
her daughters continuous fatigue, dizziness and loss of weight. The patient was 6 feet 2
inches tall and weighed 100 pounds. Further questioning revealed that the young woman had
been virtually fasting for 4 months hoping to obtain a skinny figure as a prelude to a career
in modeling.
Physical examination revealed dehydration and a fruity odor in her breath.
Laboratory results revealed Blood glucose 50 mg%.
Which substance would most likely be detected in abnormally high concentration upon
patients urine test?
A. Protein
B. Hemoglobin
C. Acetoacetate
D. Lactate
E. Pyruvate
The correct answer is- Acetoacetate.
The patient shows many signs of Anorexia Nervosa (AN), which is an eating disorder.
The etiology of AN is unknown but appears to involve a combination of psychological,
biologic, and cultural risk factors. The condition is characterized by aversion to food that
leads to a state of fasting and emaciation. Patients often have a distorted image of their own
body weight or shape and are unconcerned by the serious health consequences of their low
weight. As weight loss progresses, the fear of gaining weight grows; dieting becomes
stricter; and psychological, behavioral, and medical aberrations increase.
Metabolic alterations
Blood glucose homeostasis
Liver glycogen is exhausted in the first day of fasting. After several months of near
starvation, the blood glucose in these patients is maintained by gluconeogenesis, primarily
from amino acids mobilized from tissue proteins (figure-1). The impaired conversion of
amino acids in to glucose is responsible for producing hypoglycemia in these patients.

Figure-1- All the intermediates of TCA cycle, beyond - Ketoglutarate are glucogenic, since
they ultimately produce oxaloacetate which is channeled towards pathway of
gluconeogenesis. Acetyl co A is not glucogenic, as firstly the conversion of pyruvate to
Acetyl Co A is irreversible and secondly, in TCA cycle, it loses both of its carbons in the
form of CO2, hence it has nothing to contribute to Glucose production.
97. A 32-year-old body builder has decided to go on a diet consisting of egg whites to ensure
only proteins for muscle growth. After a few weeks he experiences decreased energy and is
found to be hypoglycemic. A nutritionist tells the patient that he most likely has the
deficiency of vitamin Biotin. Which of the following enzymes is unable to catalyze its step
in synthesizing glucose from pyruvate?
A.
B.
C.
D.
E.

Pyruvate carboxylase
Phospho enol pyruvate carboxy kinase
Glucose-6-phosphatase
Fructose 1, 6 bisphosphatase
Phosphoglycerate kinase.

The correct answer is- A) Pyruvate carboxylase.


Biotin deficiency is very common in bodybuilders, who consume raw egg whites. The Raw egg
whites contain Avidin, a glycoprotein that strongly binds with biotin and prevents its absorption.
Once a biotin-Avidin complex forms, the bond is essentially irreversible; the biotin-Avidin
complex is not broken during passage of the food bolus through the stomach and intestines. As
a result, biotin is not liberated from food, and the biotin-Avidin complex is lost in the feces.
Thus, the ingestion of large quantities of raw egg white over a long period can result in a biotin
deficiency. Cooking egg white denatures Avidin, rendering it susceptible to digestion and
therefore unable to prevent the absorption of dietary biotin.
Biotin functions to transfer carbon dioxide in a small number of carboxylation reactions. Biotin
is attached at the active site of carboxylases.

98. Skin fibroblasts incubated with radioactive amino acids synthesize polypeptide chains that
assemble to form a triple helix. Which of the following amino acids is most avidly consumed
by the fibroblasts?
A. Lysine
B. Proline
C. Alanine
D. Glycine
E. Leucine
F. Cysteine
Collagen is the most abundant protein in the human body The collagen molecule consists of
three polypeptide alpha chains held together by hydrogen bonds to form a rope-like triple helix.
Collagen is synthesized in fibroblasts, osteoblasts, and chondroblasts. The collagen molecule
has a triple helical conformation because each of the alpha chains has a simple, repetitive amino
acid sequence in which glycine (Gly) appears at every third amino acid position. The amino
acid sequence of collagen is, therefore, designated (-Gly-X-Y-)333' To fold into a triple helix,
every third amino acid in each alpha chain must be glycine Glycine is the smallest amino acid
and it fits into the restricted space that exists when three alpha chai ns come together to form a
tri pie helix.
Many of the amino acids designated X and Yare proline residues. Proline is essential for the
formation of the alpha helix because its ring structure introduces a bend into the polypeptide
chains. Other X and Y amino acids form clusters of hydrophobic and charged regions on the
surface of the molecule that enables crosslinking to other collagen molecules. Lysine is
commonly used in collagen for this purpose
Glycine is the most abundant amino acid in the collagen molecule. It occurs in AT LEAST
every third amino acid position. The amino acid formula of collagen is (-Gly-X-Y-)333
99. Hepatocytes exposed to an external stimulus demonstrate a rapid increase in intracellular
glycogen stores and a decrease in glucose release into the blood. Which of the following most
likely promotes the effects described above?
A.
B.
C.
D.
E.

Protein phosphatase-1
Protein kinase A
Phospholipase C
Janus protein kinase (JAK)
Lipoxygenase

The response of the hepatocytes to the stimulus described in the question stem is characteristic
of the response of these cells to insulin. Insulin is an anabolic hormone that promotes the
synthesis of glycogen, triacylglycerides, nucleic acids, and proteins. Insulin inhibits
glycogenolysis and gluconeogenesis. Insulin acts via a tyrosine kinase mechanism. The insulin
cell surface receptor is a transmembrane protein that also has Cytosolic tyrosine kinase activity.

The tyrosine kinase causes phosphorylation of a poorly characterized class of proteins known as
insulin receptor substrates leading to activation of protein phosphatase. Protein phosphatase
dephosphorylates glycogen synthase thereby activating that protein and promoting glycogen
synthesis. Protein phosphatase also dephosphorylates fructose 1,6-bisphosphatase thereby
inactivating that enzyme and inhibiting gluconeogenesis. This is also a good example of how
phosphorylation and dephosphorylation of enzymes by second-messenger proteins
can cause activation of some enzymes and inactivation of others.
Insulin is an anabolic hormone that acts via a tyrosine kinase second messenger system to
stimulate the synthesis of glycogen, proteins, fatty acids and nucleic acids. Tyrosine kinase
leads to the activation of protein phosphatase within cells, and protein phosphatase directly
modulates the activity of enzymes in the metabolic pathways regulated by insulin.
100. A 79-year-old female presents to your office with leg pain and fatigue She lives alone and
has little money to spend on food. The patient has tibial subperiosteal hematomas and
painful gums.
Which of the following nutrient deficiencies is most likely responsible for this patient's
symptoms?
A.
Vitamin B1
B.Vitamin B2
C.
Pyridoxine
D.
Folic acid
E.Ascorbic acid
F. Vitamin K
G.
Zinc
Vitami n C cannot be synthesized endogenously and therefore must be consumed in the human
diet. This is typically not a problem, as ascorbic acid is abundantly found in fruits and
vegetables (whiIe also being present to a lesser extent in milk, liver, and fish). Deficiencies of
vitamin C are therefore rare in developed countries, but continue to be a concern in those with
inconsistent eating patterns - including the elderly, alcoholics, and persons who live alone.
Vitamin C (ascorbic acid) deficiency eventually results in scurvy, a disease characterized by
hemorrhages, subperiosteal hematomas, bleeding into joint spaces, gingival swelling, secondary
periodontal infection, anemia, hyperkeratotic papular rashes, impaired wound healing, and
weakened immune response to local infections.
Because ascorbic acid accelerates hydroxylation and amidation reactions, it plays a crucial role
in numerous biosynthetic pathways. One of the most important functions of ascorbic acid is its
activation of prolyt and IysyI hydroxylase precursors, both of which are necessary for the
hydroxylation of procollagen. As collagen contains considerable hydroxyproline, the quantity
and quality of the collagen produced is dramatically impaired by any reduction in available
ascorbic acid.
The symptoms of scurvy are primarily caused by impaired collagen formation, and include
hemorrhages, subperiosteal hematomas, bleeding into joint spaces, gingival swelling, secondary

periodontal infection, anemia, hyperkeratotic papular rashes, impaired wound healing, and
weakened immune response to local infections.