1. A 2-year-old child presents to the clinic with failure to thrive and megaloblastic anemia. Laboratory tests reveal elevated urinary orotic acid levels but normal ammonia levels, normal CSF glutamine levels, and normal serum vitamin B12 and folate levels. Which enzyme deficiency is the most likely cause of this child’s condition?
A. Adenosine deaminase
B. Glutamine PRPP amidotransferase
C. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
D. Ornithine transcarbamoylase
E. UMP synthase
Correct Answer: E. UMP synthase
Explanation:
• UMP synthetase deficiency causes orotic aciduria, characterized by megaloblastic anemia, unresponsive to B12 or folate, failure to thrive, and elevated urinary orotic acid levels.
• This enzyme is crucial in the de novo pyrimidine synthesis pathway, converting orotic acid to UMP.
• Normal ammonia levels help distinguish UMP synthetase deficiency from urea cycle defects (e.g., OTC deficiency).
Incorrect Options:
A. Adenosine deaminase:
This enzyme is involved in purine metabolism. Its deficiency causes SCID (Severe Combined Immunodeficiency) but does not lead to orotic aciduria or megaloblastic anemia.
B. Glutamine PRPP amidotransferase:
This enzyme is involved in purine biosynthesis. Its deficiency leads to issues in purine metabolism, not pyrimidine synthesis, and does not result in orotic aciduria.
C. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT):
HGPRT deficiency causes Lesch-Nyhan syndrome, characterized by hyperuricemia, self-mutilation, and neurological symptoms, not elevated orotic acid or megaloblastic anemia.
D. Ornithine transcarbamoylase:
OTC deficiency leads to hyperammonemia and elevated urinary orotic acid due to urea cycle dysfunction. However, normal ammonia levels rule this out in this case.
Key Takeaway:
UMP synthetase deficiency is the likely cause of orotic aciduria with megaloblastic anemia and normal ammonia levels, distinguishing it from urea cycle defects and other metabolic disorders.
2. Feedback inhibition of pyrimidine nucleotide synthesis can occur by which of the following mechanisms?
A. CTP and UTP allosteric effects
B. Increased activity of Aspartate transcarbamoylase
C. Increased activity of Carbamoyl phosphate synthetase
D. TTP allosteric effects
E. UMP competitive inhibition
Correct Answer: A. CTP allosteric effects
Explanation:
• CTP (cytidine triphosphate) acts as an allosteric inhibitor of aspartate transcarbamoylase (ATCase), and UTP is an inhibitor of Carbamoyl Phosphate synthetase-II, the key enzymes in the de novo pyrimidine synthesis pathway.
• This feedback inhibition ensures the balance of nucleotide pools by slowing down pyrimidine synthesis when sufficient CTP or UTP are present.
Incorrect Options:
B. Increased activity of Aspartate transcarbamoylase:
Increased activity would promote pyrimidine synthesis, not inhibit it. Feedback inhibition by CTP decreases the activity of this enzyme.
C. Increased activity of Carbamoyl phosphate synthetase:
Carbamoyl phosphate synthetase II is involved in the first step of pyrimidine synthesis, but its increased activity would enhance, not inhibit, the pathway.
D. TTP allosteric effects:
TTP (thymidine triphosphate) is involved in DNA synthesis regulation and does not act as a feedback inhibitor in the pyrimidine nucleotide synthesis pathway.
E. UMP competitive inhibition:
UMP regulates pyrimidine biosynthesis at the level of UMP synthase (inhibiting orotate to UMP conversion), but this is not a feedback inhibition mechanism in the broader pathway.
Key Takeaway:
CTP provides feedback inhibition by allosterically inhibiting aspartate transcarbamoylase, regulating pyrimidine synthesis, and ensuring nucleotide homeostasis.
3. Which base derivative can serve as a precursor for the synthesis of two other pyrimidine base derivatives?
A. Cytidine triphosphate
B. Uridine monophosphate
C. Adenosine monophosphate
D. Deoxythymidine monophosphate
E. Deoxyadenosine monophosphate
Correct Answer: B. Uridine monophosphate
Explanation:
• Uridine monophosphate (UMP) is a key precursor in the pyrimidine nucleotide synthesis pathway.
• UMP is synthesized in the de novo pathway and serves as the precursor for:
1. Cytidine triphosphate (CTP): UMP is converted to UTP, which is then aminated to form CTP.
2. Deoxythymidine monophosphate (dTMP): UMP is converted to deoxy-UMP (dUMP), which is methylated by thymidylate synthase to produce dTMP.
Thus, UMP acts as the starting molecule for the synthesis of both CTP and dTMP.
Incorrect Options:
A. Cytidine triphosphate (CTP):
CTP is synthesized from UTP, but it does not serve as a precursor for dTMP.
C. Adenosine monophosphate (AMP):
AMP is a purine nucleotide and is unrelated to the pyrimidine synthesis pathway.
D. Deoxythymidine monophosphate (dTMP):
dTMP is synthesized from dUMP and is not a precursor for other pyrimidines.
E. Deoxyadenosine monophosphate (dAMP):
dAMP is a purine nucleotide, unrelated to the pyrimidine synthesis pathway.
Key Takeaway:
Uridine monophosphate (UMP) is the central precursor for the synthesis of the pyrimidine nucleotides CTP and dTMP, highlighting its pivotal role in nucleotide metabolism.
4. Which of the following can inhibit purine nucleotide biosynthesis?
A. Guanosine triphosphate
B. Uridine monophosphate
C. Adenosine monophosphate
D. Adenosine triphosphate
E. Inosine diphosphate
Correct Answer: C. Adenosine monophosphate
Explanation:
• Adenosine monophosphate (AMP) acts as a feedback inhibitor in purine nucleotide biosynthesis.
• Glutamine PRPP amidotransferase, the rate-limiting enzyme in de novo purine synthesis, is inhibited by the end products AMP and GMP, ensuring nucleotide balance.
• This feedback inhibition prevents the excessive production of purine nucleotides.
Incorrect Options:
A. Guanosine triphosphate (GTP):
While GTP is required for AMP synthesis, it does not inhibit the purine biosynthesis pathway.
B. Uridine monophosphate (UMP):
UMP is a pyrimidine nucleotide and does not regulate purine nucleotide biosynthesis.
D. Adenosine triphosphate (ATP):
ATP acts as a substrate for purine biosynthesis and is not an inhibitor.
E. Inosine diphosphate (IDP):
Inosine diphosphate is an intermediate in purine metabolism and does not inhibit the pathway.
Key Takeaway:
The purine nucleotide biosynthesis pathway is regulated by feedback inhibition through the end products AMP and GMP, which inhibit the rate-limiting enzyme glutamine PRPP amidotransferase.
5. The blood chemistry of a 6-year-old child shows serum uric acid levels of 1.5 mg/dl, which is considered low. Which of the following conditions might be the reason for this state?
A. Lesch-Nyhan syndrome
B. Adenosine deaminase deficiency
C. Overactivity of PRPP synthetase
D. Overactivity of amidotransferase
E. von Gierke’s disease
Correct Answer: B. Adenosine deaminase deficiency
Explanation:
• Adenosine deaminase (ADA) deficiency is primarily associated with severe combined immunodeficiency (SCID) due to its role in purine metabolism. ADA deficiency leads to an accumulation of deoxyadenosine, which inhibits ribonucleotide reductase, reducing DNA synthesis in lymphocytes.
• However, it also impacts purine metabolism more broadly, leading to decreased breakdown of nucleotides into uric acid. Thus, ADA deficiency can result in lower than normal uric acid levels.
Incorrect Options:
A. Lesch-Nyhan syndrome:
Lesch-Nyhan syndrome is characterized by high uric acid levels due to a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT), leading to overproduction of uric acid, not reduced levels.
C. Overactivity of PRPP synthetase:
Overactivity of phosphoribosyl pyrophosphate (PRPP) synthetase leads to increased purine synthesis and, subsequently, higher uric acid levels, contrary to what is observed in this case.
D. Overactivity of amidotransferase:
Overactivity of glutamine-PRPP amidotransferase would also typically result in increased purine synthesis and higher uric acid levels.
E. von Gierke’s disease:
von Gierke’s disease, or glycogen storage disease type I, primarily affects glucose metabolism due to a deficiency in glucose-6-phosphatase. It can lead to high uric acid levels due to increased purine turnover from impaired carbohydrate metabolism and lactic acidemia, not low levels.
Key Takeaway:
Low uric acid levels in a child can be indicative of metabolic disturbances affecting purine breakdown, with adenosine deaminase deficiency being a plausible cause due to its impact on purine metabolism and subsequent reduction in uric acid production.
6. A 4-year-old presents to a pediatric clinic with megaloblastic anemia and failure to thrive. Blood biochemistry reveals “orotic aciduria.” Enzyme measurement of white blood cells shows a deficiency in the pyrimidine biosynthesis enzyme orotate phosphoribosyl transferase and abnormally high activity of aspartate transcarbamoylase. Which of the following treatments will reverse all symptoms?
A. Blood transfusion
B. Dietary supplementation of PRPP
C. Oral thymidine
D. Oral uridine
E. Plasmapheresis
Correct Answer: D. Oral uridine
Explanation:
• The child’s symptoms are consistent with hereditary orotic aciduria, a rare genetic disorder caused by a deficiency in UMP synthase (a bifunctional enzyme that includes orotate phosphoribosyl transferase and orotidine-5′-decarboxylase).
• This deficiency leads to the accumulation of orotic acid and impaired pyrimidine nucleotide synthesis, resulting in megaloblastic anemia unresponsive to vitamin B12 or folate.
• Oral uridine supplementation bypasses the metabolic block by providing an external source of uridine, which is converted to UMP and subsequently supports pyrimidine synthesis. This reverses the symptoms of megaloblastic anemia and promotes normal growth.
Incorrect Options:
A. Blood transfusion:
While blood transfusion may temporarily alleviate anemia, it does not address the underlying metabolic defect, so other symptoms like failure to thrive will persist.
B. Dietary supplementation of PRPP:
Increasing PRPP would not bypass the enzyme deficiency and might exacerbate the condition by increasing substrate (orotic acid) accumulation.
C. Oral thymidine:
Thymidine is not a direct precursor for UMP and cannot correct the pyrimidine synthesis block caused by UMP synthase deficiency.
E. Plasmapheresis:
Plasmapheresis is not relevant for hereditary orotic aciduria, as it does not address the metabolic defect or its consequences.
Key Takeaway:
Oral uridine supplementation is the specific treatment for hereditary orotic aciduria, as it bypasses the metabolic block in pyrimidine synthesis, correcting both anemia and growth failure.
7. Which of the following is a structural analog of hypoxanthine?
A. Arabinoside C
B. Allopurinol
C. Ribose phosphate
D. PRPP
E. 5-Fluorouracil
Correct Answer: B. Allopurinol
Explanation:
• Allopurinol is a structural analog of hypoxanthine, a purine base.
• It is used as a therapeutic agent in the treatment of gout and hyperuricemia by inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and uric acid.
• Its structural similarity allows it to act as a competitive inhibitor and reduce uric acid production.
Incorrect Options:
A. Arabinoside C:
This is a cytosine analog used as an antiviral and chemotherapeutic agent, not related to hypoxanthine.
C. Ribose phosphate:
Ribose phosphate is part of the structure of nucleotides but is not an analog of hypoxanthine.
D. PRPP (Phosphoribosyl pyrophosphate):
PRPP is a substrate in purine and pyrimidine nucleotide synthesis but is not an analog of hypoxanthine.
E. 5-Fluorouracil (5-FU):
5-FU is a pyrimidine analogue, specifically of uracil, used in cancer therapy, and is unrelated to hypoxanthine.
Key Takeaway:
Allopurinol is a hypoxanthine analog used clinically to manage gout by reducing uric acid production through the inhibition of xanthine oxidase.
8. A pentose with a 5′ phosphate group, a 2′ OH group, and an attached 1′ pyrimidine group describes which of the following structures?
A. Cytosine
B. Thymidine
C. Thymidylate
D. Cytidylate
E. Guanosine
Correct Answer: D. Cytidylate
Explanation:
• The described structure is a ribonucleotide because it contains a 2′ OH group on the sugar (ribose).
• The 1′ pyrimidine group indicates that the nitrogenous base is either cytosine or uracil (since pyrimidines include cytosine, uracil, and thymine).
• The presence of a 5′ phosphate group confirms that it is a nucleotide (not a nucleoside).
• Among the options, cytidylate (CMP) fits the description, consisting of a ribose sugar, cytosine base, and a phosphate group attached to the 5′ position.
Incorrect Options:
A. Cytosine:
Cytosine is just the pyrimidine base and lacks the ribose and phosphate group described in the question.
B. Thymidine:
Thymidine is a nucleoside, not a nucleotide, and contains thymine (a pyrimidine) attached to deoxyribose, which lacks a 2′ OH group.
C. Thymidylate:
Thymidylate (TMP) is a nucleotide containing deoxyribose (without a 2′ OH group) and thymine. It does not match the description of a ribonucleotide.
E. Guanosine:
Guanosine is a nucleoside (not a nucleotide) with a purine base (guanine), not a pyrimidine base.
Key Takeaway:
Cytidylate (CMP) is a ribonucleotide containing a ribose sugar, a cytosine base (pyrimidine), and a phosphate group at the 5′ position.
9. Which of the following enzymes is inhibited by uridine triphosphate (UTP)?
A. Aspartate transcarbamoylase
B. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
C. Thymidylate synthase
D. Carbamoyl phosphate synthetase-II
E. PRPP synthetase
Correct Answer: D. Carbamoyl phosphate synthetase-II
Explanation:
• Carbamoyl phosphate synthetase-II (CPS-II) is the rate-limiting enzyme in the de novo pyrimidine nucleotide biosynthesis pathway.
• UTP inhibits CPS-II through feedback inhibition to regulate the pathway and prevent excess pyrimidine nucleotide production.
• When UTP levels are sufficient, CPS-II activity is reduced, ensuring balanced nucleotide synthesis.
Incorrect Options:
A. Aspartate transcarbamoylase:
o This enzyme is regulated allosterically but is inhibited by CTP, not UTP.
B. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT):
o HGPRT is involved in the purine salvage pathway and is not regulated by UTP.
C. Thymidylate synthase:
o This enzyme is involved in the conversion of dUMP to dTMP during DNA synthesis and is not affected by UTP.
E. PRPP synthetase:
o PRPP synthetase is involved in the synthesis of PRPP and is regulated by purine and pyrimidine nucleotides, but UTP does not inhibit this enzyme specifically.
Key Takeaway:
UTP inhibits Carbamoyl phosphate synthetase-II (CPS-II) through feedback inhibition, helping regulate pyrimidine nucleotide biosynthesis.
10. A 5-year-old boy is brought to the pediatric emergency room in an unconscious state. His blood ammonia and CSF glutamine levels are elevated, while blood urea levels are low. Urine analysis reveals the presence of orotic acid. There is no history of growth retardation or any other illness in the past, but he has been hospitalized several times with similar symptoms. Which of the following enzyme deficiencies might be expected in this child?
A. UMP synthase
B. G6 Phosphate dehydrogenase
C. Ornithine transcarbamoylase
D. HGPRT
E. NAG synthase
Correct Answer: C. Ornithine transcarbamoylase
Explanation:
• Ornithine transcarbamoylase (OTC) deficiency is the most common urea cycle disorder and is X-linked recessive.
• OTC catalyzes the conversion of carbamoyl phosphate and ornithine into citrulline in the urea cycle.
• In OTC deficiency:
1. Ammonia accumulates due to impaired urea cycle activity, causing hyperammonemia.
2. Elevated ammonia leads to increased CSF glutamine, as ammonia is detoxified into glutamine.
3. Carbamoyl phosphate accumulates and spills into the pyrimidine biosynthesis pathway, resulting in orotic aciduria.
This combination of hyperammonemia, elevated CSF glutamine, and orotic aciduria strongly suggests OTC deficiency.
Incorrect Options:
A. UMP synthase:
o Deficiency causes hereditary orotic aciduria, characterized by orotic aciduria, megaloblastic anemia, and growth retardation.
o However, ammonia and glutamine levels remain normal in UMP synthase deficiency, unlike in urea cycle disorders.
B. G6 Phosphate dehydrogenase (G6PD):
o G6PD deficiency affects the pentose phosphate pathway and leads to hemolytic anemia under oxidative stress.
o It does not cause hyperammonemia, orotic aciduria, or elevated CSF glutamine.
D. HGPRT (Hypoxanthine-guanine phosphoribosyltransferase):
o Deficiency causes Lesch-Nyhan syndrome, a disorder of purine metabolism characterized by hyperuricemia, self-mutilation, and neurological symptoms.
o It does not cause hyperammonemia or orotic aciduria.
E. NAG synthase (N-acetylglutamate synthase):
o NAG synthase deficiency is a urea cycle disorder that impairs carbamoyl phosphate synthetase I (CPS-I) activation, leading to hyperammonemia.
o However, this condition does not cause orotic aciduria, as carbamoyl phosphate does not accumulate excessively.
Key Takeaway:
The combination of hyperammonemia, elevated CSF glutamine, low blood urea, and orotic aciduria strongly suggests Ornithine transcarbamoylase (OTC) deficiency, a urea cycle disorder with pyrimidine biosynthesis involvement.
11. A medical biochemist during his lecture, asks his students about a 2-year-old child with classical galactosemia who exhibits higher activity of AMP deaminase. Which of the following might be the outcome of this overactivity?
A. Hypouricemia
B. Hyperuricemia
C. Orotic aciduria
D. Galactosuria
E. Ketonuria
Correct Answer: B. Hyperuricemia
Explanation:
• AMP deaminase catalyzes the conversion of AMP to inosine monophosphate (IMP), which enters the purine degradation pathway.
• Increased AMP deaminase activity leads to excessive degradation of AMP, resulting in elevated levels of uric acid as the end product of purine metabolism.
• In classical galactosemia, metabolic stress due to galactose-1-phosphate accumulation can activate AMP deaminase, enhancing purine catabolism and causing hyperuricemia.
Incorrect Options:
A. Hypouricemia:
o Overactivity of AMP deaminase would increase uric acid production, not decrease it.
C. Orotic aciduria:
o Orotic aciduria results from defects in pyrimidine synthesis or urea cycle disorders (e.g., OTC deficiency), not from increased AMP deaminase activity.
D. Galactosuria:
o Galactosuria is a hallmark of classical galactosemia due to the inability to properly metabolize galactose. However, it is unrelated to AMP deaminase overactivity.
E. Ketonuria:
o Ketonuria occurs in metabolic states such as prolonged fasting, uncontrolled diabetes, or ketogenic diets. It is not a consequence of AMP deaminase overactivity.
Key Takeaway:
Increased activity of AMP deaminase in a child with classical galactosemia can lead to hyperuricemia due to enhanced purine catabolism, resulting in excessive production of uric acid.
12. An 8-year-old child with hereditary fructose intolerance is brought to the pediatric office with stiffness of joints. His mother informs that he is non-compliant with dietary restrictions and continues to consume sweets, chocolates, and candies. Blood chemistry reveals elevated uric acid levels. Which of the following statements best explains the reason for hyperuricemia in this child resulting from Aldolase B deficiency?
A. Overactivity of PRPP synthetase
B. Increased activity of Adenosine deaminase
C. Increased activity of AMP deaminase
D. Increased synthesis of purine nucleotides
E. Impaired excretion of uric acid
Correct Answer: C. Increased activity of AMP deaminase
Explanation:
• Aldolase B deficiency in hereditary fructose intolerance leads to the accumulation of fructose-1-phosphate in liver cells.
• This accumulation depletes intracellular ATP stores, as phosphate is trapped in fructose-1-phosphate.
• The drop in ATP triggers the activation of AMP deaminase, which converts AMP (a precursor of ATP) to IMP, eventually leading to excessive uric acid production through purine degradation.
• The resulting hyperuricemia is a key metabolic complication in hereditary fructose intolerance when dietary fructose is not avoided.
Incorrect Options:
A. Overactivity of PRPP synthetase:
o Overactivity of PRPP synthetase would lead to increased purine synthesis and uric acid levels but is not associated with Aldolase B deficiency.
B. Increased activity of Adenosine deaminase:
o Adenosine deaminase plays a role in purine metabolism, but its increased activity is not linked to hyperuricemia caused by Aldolase B deficiency.
D. Increased synthesis of purine nucleotides:
o Aldolase B deficiency does not directly increase purine nucleotide synthesis. Instead, it increases purine degradation via AMP depletion.
E. Impaired excretion of uric acid:
o Hyperuricemia in this condition is due to increased production of uric acid, not impaired excretion.
Key Takeaway:
In hereditary fructose intolerance, hyperuricemia results from increased AMP deaminase activity due to ATP depletion caused by the accumulation of fructose-1-phosphate, leading to enhanced purine degradation and uric acid production.
13. A 6-year-old girl is brought to the pediatric emergency room in a semi-conscious state. Blood chemistry reveals hypoglycemia, ketoacidosis, and hyperuricemia. She is found to have reduced activity of glucose-6-phosphatase. Which of the following statements best describes the most important reason for hyperuricemia in this patient?
A. Overactivity of Xanthine oxidase
B. Increased synthesis as well as degradation of purine nucleotides
C. Increased synthesis of uric acid
D. Impaired excretion of uric acid
E. Increased synthesis and impaired excretion of uric acid
Correct Answer: E. Increased synthesis and impaired excretion of uric acid
Explanation:
• Glucose-6-phosphatase deficiency (von Gierke’s disease) leads to hyperuricemia through two major mechanisms:
Mechanisms Behind Hyperuricemia in von Gierke’s Disease
1. Increased Entry of Glucose-6-Phosphate into the HMP Pathway:
o In glucose-6-phosphatase deficiency, glucose-6-phosphate (G6P) cannot be converted to free glucose for release into the blood.
o Excess G6P is shunted into the HMP pathway, leading to an overproduction of ribose-5-phosphate, a precursor for PRPP synthesis.
2. Increased PRPP Levels:
o Elevated PRPP stimulates de novo purine nucleotide synthesis, leading to an overproduction of purines.
3. Increased Purine Degradation:
o The excessive purines synthesized are degraded into uric acid, as the body’s mechanisms for nucleotide recycling and utilization become saturated.
o This results in increased uric acid synthesis.
4. Impaired Uric Acid Excretion Due to Lactic Acidosis:
o The accumulation of lactate (a byproduct of glycolysis) competes with uric acid for renal excretion, reducing uric acid clearance and further exacerbating hyperuricemia.
Incorrect Options:
A. Overactivity of Xanthine oxidase:
o Xanthine oxidase activity is not inherently overactive in von Gierke’s disease. The increased uric acid production is secondary to excessive purine breakdown.
B Increased synthesis as well as degradation of purine nucleotides
o While increased synthesis and purine degradation is correct, it does not address the equally important role of impaired excretion in hyperuricemia caused by lactate competition.
C. Increased synthesis of uric acid:
o This option is partially correct but does not account for impaired excretion, which is a key contributor to hyperuricemia in this condition.
D. Impaired excretion of uric acid:
o Impaired excretion alone does not fully explain the hyperuricemia; increased synthesis due to purine degradation is equally important.
Key Takeaway:
In glucose-6-phosphatase deficiency, hyperuricemia is caused by a combination of increased uric acid synthesis due to excessive purine degradation and impaired uric acid excretion due to lactate accumulation, making Option E the most comprehensive and accurate choice.
14. A 58-year-old man is awoken by a throbbing ache in his great toe. He had a similar attack after indulging in a rich meal. On examination, he is noted to have an inflamed great toe and several nodules on the antihelix of his ear. Inhibition of which of the following enzymes might prevent the occurrence of such symptoms?
A. Glutamine PRPP Amidotransferase
B. PRPP Synthetase
C. Xanthine Oxidase
D. Orotate Phosphoribosyltransferase
Correct Answer: C. Xanthine Oxidase
Explanation:
• The patient presents with acute gouty arthritis, a condition caused by the accumulation of uric acid crystals in joints and tissues.
• Xanthine oxidase is the enzyme that converts hypoxanthine to xanthine and then to uric acid in the purine degradation pathway.
• Inhibitors of xanthine oxidase, such as allopurinol or febuxostat, reduce uric acid production and prevent the formation of urate crystals, thereby preventing symptoms of gout.
Incorrect Options:
A. Glutamine PRPP Amidotransferase:
o This enzyme is the rate-limiting step in de novo purine synthesis. While its inhibition might reduce uric acid production by limiting purine synthesis, it is not the primary therapeutic target in gout management.
B. PRPP Synthetase:
o PRPP synthetase is involved in the production of PRPP, a substrate for purine and pyrimidine synthesis. Its overactivity can lead to overproduction of purines and uric acid, but it is not a direct therapeutic target for gout.
D. Orotate Phosphoribosyltransferase:
o This enzyme is part of the pyrimidine biosynthesis pathway and is unrelated to uric acid production or gout pathophysiology.
Key Takeaway:
In gout, xanthine oxidase inhibition reduces uric acid production, alleviating and preventing symptoms. Medications like allopurinol target this enzyme to manage acute attacks and prevent chronic urate crystal deposition.
15. A medical biochemist, while discussing Adenosine Deaminase (ADA) deficiency, mentioned the “Bubble Baby” syndrome to describe the immunocompromised state associated with this condition. To assess knowledge retention, he asked the students: which of the following conversions might be affected in this patient?
A. AMP to IMP
B. Xanthine to Uric Acid
C. Hypoxanthine to Uric Acid
D. Adenosine to Inosine
E. XMP to GMP
Correct Answer: D. Adenosine to Inosine
Explanation :
• Adenosine deaminase (ADA) catalyzes the deamination of adenosine to inosine and deoxyadenosine to deoxyinosine in the purine salvage pathway.
• In ADA deficiency:
1. Adenosine and deoxyadenosine accumulate, leading to toxic levels, especially in lymphocytes.
2. Deoxyadenosine is converted to dATP, which inhibits ribonucleotide reductase, impairing DNA synthesis and leading to the failure of lymphocyte development.
o This results in Severe Combined Immunodeficiency (SCID), commonly referred to as “Bubble Baby” syndrome.
Incorrect Options:
A. AMP to IMP:
o This conversion is catalyzed by AMP deaminase, not ADA. ADA deficiency does not affect this pathway.
B. Xanthine to Uric Acid:
o This step is catalyzed by xanthine oxidase, which is not affected by ADA deficiency.
C. Hypoxanthine to Uric Acid:
o This step is also catalyzed by xanthine oxidase and is not directly influenced by ADA deficiency.
E. XMP to GMP:
o This conversion is catalyzed by GMP synthetase in the purine synthesis pathway and is unrelated to ADA activity.
Key Takeaway:
The adenosine to inosine conversion is directly affected in Adenosine Deaminase (ADA) deficiency, leading to the toxic accumulation of adenosine and deoxyadenosine, which causes the immunocompromised state seen in SCID.
16. The medical biochemist further asked about the basis of the immunocompromised state in Adenosine Deaminase (ADA) deficiency. Which of the following best describes this state?
A. Reduced conversion of dUMP to TMP
B. Reduced conversion of DHFR to THFR
C. Inhibition of DNA polymerase by AMP
D. Inhibition of ribonucleotide reductase by dATP
E. Inhibition of IMP dehydrogenase by AMP
Correct Answer: D. Inhibition of ribonucleotide reductase by dADP
Explanation:
• In ADA deficiency, deoxyadenosine (dAdP) accumulates due to the impaired conversion of adenosine to inosine.
• Deoxyadenosine is phosphorylated to deoxyadenosine triphosphate (dATP), which accumulates to toxic levels in lymphocytes.
• dATP strongly inhibits ribonucleotide reductase, the enzyme responsible for converting ribonucleotides to deoxyribonucleotides.
• This inhibition prevents the synthesis of other deoxyribonucleotides (e.g., dCTP, dGTP, dTTP), which are essential for DNA replication and repair.
• The lack of DNA synthesis impairs the development and proliferation of T cells and B cells, leading to severe combined immunodeficiency (SCID).
Incorrect Options:
A. Reduced conversion of dUMP to TMP:
o This step is catalyzed by thymidylate synthase in pyrimidine synthesis and is not directly affected in ADA deficiency.
B. Reduced conversion of DHFR to THFR:
o This step involves dihydrofolate reductase (DHFR), a key enzyme in folate metabolism, and is unrelated to ADA deficiency.
C. Inhibition of DNA polymerase by AMP:
o DNA polymerase activity is not inhibited by AMP. The toxic effect in ADA deficiency is due to the accumulation of dATP, not AMP.
E. Inhibition of IMP dehydrogenase by AMP:
o AMP does inhibit IMP dehydrogenase in purine synthesis, but this is unrelated to the immunocompromised state seen in ADA deficiency.
Key Takeaway:
The immunocompromised state in ADA deficiency results from the accumulation of dATP, which inhibits ribonucleotide reductase, leading to a failure of DNA synthesis and lymphocyte development.
17. A 45-year-old woman troubled by her 6-year-old son’s bizarre behavior of head banging, lip biting, and hair pulling has reported to the pediatric OPD. As a physician, she suspects Lesch-Nyhan syndrome as the diagnosis. Which of the following enzyme estimations might be helpful in confirming the diagnosis?
A. Glutamine PRPP Amidotransferase
B. PRPP Synthetase
C. HGPRT
D. APRT
E. UMP Synthase
Correct Answer: C. HGPRT
Explanation:
• Lesch-Nyhan syndrome is a rare X-linked recessive disorder caused by a complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
• HGPRT is a key enzyme in the purine salvage pathway, catalyzing the conversion of hypoxanthine to IMP and guanine to GMP using PRPP as a substrate.
• In its absence:
o Purines accumulate and are degraded to uric acid, leading to hyperuricemia.
o The lack of salvage leads to overactivation of de novo purine synthesis, further increasing uric acid levels.
• The characteristic clinical features include:
o Self-mutilation behaviors (e.g., head banging, lip biting, hair pulling).
o Neurological symptoms (spasticity, developmental delay).
o Hyperuricemia (gout and urate crystal deposition).
Measuring HGPRT activity in fibroblasts or lymphocytes can confirm the diagnosis.
Incorrect Options:
A. Glutamine PRPP Amidotransferase:
o This enzyme is the rate-limiting step in de novo purine synthesis, but it is not directly defective in Lesch-Nyhan syndrome.
o Its overactivity in Lesch-Nyhan syndrome is secondary to excess PRPP, not due to an intrinsic defect.
B. PRPP Synthetase:
o PRPP synthetase generates PRPP, a substrate for both de novo and salvage pathways.
o Overactivity of PRPP synthetase could contribute to hyperuricemia, but it is not the primary defect in Lesch-Nyhan syndrome.
D. APRT (Adenine Phosphoribosyltransferase):
o APRT catalyzes the salvage of adenine to AMP. While it is part of the purine salvage pathway, its deficiency causes 2,8-dihydroxyadenine urolithiasis, not Lesch-Nyhan syndrome.
E. UMP Synthase:
o UMP synthase is involved in the pyrimidine biosynthesis pathway and is unrelated to purine metabolism or Lesch-Nyhan syndrome.
Key Takeaway:
The hallmark enzyme defect in Lesch-Nyhan syndrome is HGPRT deficiency, and its activity measurement is crucial for confirming the diagnosis in patients with hyperuricemia and self-mutilating behaviors.
18. In the same patient, which of the following substances might be substantially elevated in the serum?
A. Uric acid
B. Orotic acid
C. Glucose
D. Ketone bodies
E. Urea
Correct Answer: A. Uric acid
Explanation:
• Uric acid levels are significantly elevated in Lesch-Nyhan syndrome due to the deficiency of HGPRT.
• Without HGPRT, the salvage pathway for purines is impaired, leading to:
1. Excess PRPP: Stimulating de novo purine synthesis.
2. Increased purine breakdown: Resulting in overproduction of uric acid.
• The elevated uric acid causes hyperuricemia, which can lead to gout, urate crystal deposition, and kidney complications.
Incorrect Options:
B. Orotic acid:
o Elevated orotic acid is seen in pyrimidine metabolism disorders (e.g., UMP synthase deficiency or OTC deficiency) but is not associated with purine metabolism disorders like Lesch-Nyhan syndrome.
C. Glucose:
o Lesch-Nyhan syndrome does not affect glucose metabolism. Serum glucose levels would not be substantially elevated.
D. Ketone bodies:
o Elevated ketone bodies occur in metabolic states like fasting, diabetes, or inborn errors of fatty acid oxidation. It is unrelated to Lesch-Nyhan syndrome.
E. Urea:
o Urea production is linked to nitrogen metabolism. While increased purine degradation produces uric acid, it does not lead to increased urea synthesis.
Key Takeaway:
In Lesch-Nyhan syndrome, the absence of HGPRT causes hyperuricemia due to increased purine degradation and uric acid production, making uric acid the substance substantially elevated in the serum.
19. In the same patient, which of the following is most likely the mode of inheritance?
A. Autosomal recessive
B. Autosomal dominant
C. X-linked recessive
D. X-linked dominant
E. Mitochondrial
Correct Answer: C. X-linked recessive
Explanation:
• Lesch-Nyhan syndrome is inherited in an X-linked recessive pattern.
• The HPRT1 gene, encoding the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), is located on the X chromosome.
• Males with a defective HPRT1 gene are fully affected because they have only one X chromosome (hemizygous).
• Females with a defective gene are typically carriers, as their second X chromosome usually compensates for the deficiency. Carrier females are rarely affected.
Incorrect Options:
A. Autosomal recessive:
o Autosomal recessive inheritance typically affects both males and females equally and requires mutations in both copies of the gene. Lesch-Nyhan syndrome does not follow this pattern.
B. Autosomal dominant:
o Autosomal dominant disorders are caused by mutations in one copy of a gene located on an autosome. This pattern is not seen in Lesch-Nyhan syndrome.
D. X-linked dominant:
o X-linked dominant conditions affect both males and females, but females often have milder symptoms. Lesch-Nyhan syndrome does not fit this inheritance pattern.
E. Mitochondrial:
o Mitochondrial inheritance is exclusively maternal and does not involve the X chromosome or follow the patterns seen in Lesch-Nyhan syndrome.
Key Takeaway:
Lesch-Nyhan syndrome is an X-linked recessive disorder caused by a mutation in the HPRT1 gene on the X chromosome, predominantly affecting males, while females are typically carriers.
20. A 45-year-old woman, adopted from an orphanage and unsure of her family history, is concerned about the risk of her future child inheriting Lesch-Nyhan syndrome. Her husband is asymptomatic. What is the probability that her child might inherit this disorder?
A. 25%
B. 50%
C. 75%
D. 0%
E. 100%
Correct Answer: A. 25%
Explanation:
1. Lesch-Nyhan syndrome is an X-linked recessive disorder caused by a mutation in the HGPRT gene on the X chromosome.
2. For a child to inherit the disease, the following conditions must be met:
o The mother must be a carrier of the mutation.
o The child must be a son, as males are hemizygous for the X chromosome and will express the mutation if inherited.
3. Since the woman’s family history is unknown:
o There is a 50% chance she is a carrier.
o If she is a carrier, there is a 50% chance of passing the mutated X chromosome to a son, who would inherit the disease.
o This results in a combined probability of: 50%(carrier status)×50%(affected son)=25%
Key Takeaway:
Given the 50% chance the mother is a carrier and the inheritance pattern of the disorder, the probability of her future child inheriting Lesch-Nyhan syndrome is 25%. This calculation considers both her uncertain carrier status and the likelihood of the child being male and inheriting the mutation.
21. A 60-year-old female suffering from colon cancer has been prescribed a drug that inhibits TMP synthesis. TMP is an essential nucleotide, and its impaired synthesis affects DNA replication and cell division. Which of the following sets correctly identifies the drug and the enzyme it inhibits?
A. Mycophenolic acid and IMP dehydrogenase
B. Allopurinol and Xanthine oxidase
C. Methotrexate and DHFR
D. 5-Fluorouracil and Thymidylate synthase
E. 6-Mercaptopurine and DNA Polymerase
Correct Answer: D. 5-Fluorouracil and Thymidylate synthase
Explanation :
• 5-Fluorouracil (5-FU) is a chemotherapeutic agent that targets rapidly dividing cancer cells by inhibiting Thymidylate synthase, the enzyme responsible for converting dUMP to dTMP.
• This inhibition depletes dTMP, a critical precursor for DNA synthesis, which disrupts DNA replication and cell division in cancer cells.
• As a result, 5-FU is effective in treating cancers such as colon cancer, which rely on rapid cell proliferation.
Incorrect Options:
• A. Mycophenolic acid and IMP dehydrogenase:
o Mycophenolic acid inhibits IMP dehydrogenase, which reduces guanine nucleotide synthesis. This drug is used as an immunosuppressant, not a chemotherapeutic agent, and does not target TMP synthesis.
• B. Allopurinol and Xanthine oxidase:
o Allopurinol inhibits Xanthine oxidase, reducing uric acid production and managing gout. It is unrelated to TMP synthesis or cancer treatment.
• C. Methotrexate and DHFR (Dihydrofolate reductase):
o Methotrexate inhibits DHFR, preventing the production of tetrahydrofolate (THF), which is required for purine and TMP synthesis. While it indirectly affects TMP synthesis, it does not directly inhibit Thymidylate synthase.
• E. 6-Mercaptopurine and DNA Polymerase:
o 6-Mercaptopurine inhibits enzymes in the purine synthesis pathway, reducing purine nucleotide levels. It does not directly affect TMP synthesis or DNA Polymerase activity.
Key Takeaway:
5-Fluorouracil inhibits Thymidylate synthase, directly blocking TMP synthesis, disrupting DNA replication, and impeding the proliferation of rapidly dividing cancer cells such as those in colon cancer.
22. A medical student is charting metabolic defects and their associated urinary findings but misses a key defect in the de novo pathway of pyrimidine nucleotide biosynthesis caused by a deficiency of UMP synthase. Which of the following substances is most likely to be elevated in the urine in this condition?
A. Uric acid
B. Homocysteine
C. Methylmalonic acid
D. Orotic acid
E. Propionic acid
Correct Answer: D. Orotic acid
Explanation:
A deficiency in UMP synthase, a bifunctional enzyme involved in pyrimidine nucleotide biosynthesis, leads to the accumulation of orotic acid, which is excreted in the urine. This condition, known as hereditary orotic aciduria, is characterized by megaloblastic anemia, failure to thrive, and elevated urinary orotic acid levels.
Incorrect Options:
A. Uric acid:
o Elevated uric acid levels are seen in purine metabolism disorders, such as Lesch-Nyhan syndrome, not in UMP synthase deficiency.
B. Homocysteine:
o Elevated homocysteine is associated with homocystinuria, a defect in methionine metabolism, and is unrelated to pyrimidine biosynthesis.
C. Methylmalonic acid:
o Methylmalonic aciduria results from defects in methylmalonyl-CoA mutase or vitamin B12 metabolism, not nucleotide biosynthesis.
E. Propionic acid:
o Elevated propionic acid is seen in propionic acidemia, a disorder of amino acid and odd-chain fatty acid metabolism, not pyrimidine biosynthesis.
Key Takeaway:
Orotic aciduria is the characteristic urinary finding in UMP synthase deficiency, a defect in the de novo pyrimidine nucleotide biosynthesis pathway.
23. A pharmaceutical company claims to have discovered an anticancer drug that inhibits the regulatory enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. The drug is reported to act as a structural analog of the feedback inhibitor of this pathway. Which of the following sets of feedback inhibitor and enzyme is the most likely target of this drug?
A. CTP, OMP decarboxylase
B. UTP, Carbamoyl synthetase-II
C. GTP, Glutamine PRPP Amidotransferase
D. CTP, UMP synthase
E. ATP, IMP dehydrogenase
Correct Answer: B. UTP, Carbamoyl synthetase-II
Explanation:
The rate-limiting step in pyrimidine biosynthesis is catalyzed by Carbamoyl synthetase-II (CPS-II), which synthesizes carbamoyl phosphate. This enzyme is regulated by feedback inhibition from UTP (uridine triphosphate). A structural analog of UTP would mimic this feedback inhibition, reducing pyrimidine nucleotide synthesis and impairing DNA and RNA synthesis in rapidly dividing cancer cells.
Incorrect Options:
A. CTP, OMP decarboxylase:
o CTP inhibits Aspartate transcarbamoylase (ATCase), not OMP decarboxylase. OMP decarboxylase is not the rate-limiting step in pyrimidine synthesis.
C. GTP, Glutamine PRPP Amidotransferase:
o GTP does not regulate Glutamine PRPP Amidotransferase. This enzyme is the rate-limiting step in purine biosynthesis, not pyrimidine biosynthesis.
D. CTP, UMP synthase:
o CTP regulates ATCase, not UMP synthase. UMP synthase is not the rate-limiting enzyme in nucleotide biosynthesis.
E. ATP, IMP dehydrogenase:
o ATP does not regulate IMP dehydrogenase. IMP dehydrogenase is involved in purine biosynthesis, not pyrimidine synthesis.
Key Takeaway:
The rate-limiting enzyme in pyrimidine biosynthesis is Carbamoyl synthetase-II (CPS-II), which is inhibited by UTP through feedback regulation. A drug targeting this pathway would mimic UTP’s action on CPS-II to inhibit nucleotide biosynthesis and impede cancer cell proliferation.
24. A physician evaluates a 32-year-old patient for fatigue. The patient is found to have an elevated white blood cell count and an enlarged spleen. A referral to an oncologist results in a diagnosis of chronic myelogenous leukemia (CML). Treatment with hydroxyurea, a ribonucleotide reductase inhibitor, is begun. Which of the following reactions is catalyzed by this enzyme and might be affected by this intervention?
A. Xanthine to uric acid
B. ADP to dADP
C. Guanine to xanthine
D. AMP to IMP
E. PRPP to phosphoribosylamine
Correct Answer: B. ADP to dADP
Explanation:
• Ribonucleotide reductase is the enzyme responsible for converting ribonucleoside diphosphates (e.g., ADP, GDP, CDP, UDP) to their corresponding deoxyribonucleoside diphosphates (e.g., dADP, dGDP, dCDP, dUDP).
• This step is crucial for providing the deoxyribonucleotides required for DNA synthesis and replication.
• By inhibiting ribonucleotide reductase, hydroxyurea reduces the availability of deoxyribonucleotides, impairing DNA synthesis, which selectively affects rapidly dividing cells like those in CML.
• The specific reaction catalyzed by this enzyme in the question is ADP → dADP.
Incorrect Options:
A. Xanthine to uric acid:
o This reaction is catalyzed by xanthine oxidase, not ribonucleotide reductase. It is part of purine degradation, not nucleotide synthesis.
C. Guanine to xanthine:
o This reaction is also part of purine degradation and is catalyzed by guanine deaminase, not ribonucleotide reductase.
D. AMP to IMP:
o This reaction is catalyzed by AMP deaminase and is unrelated to the role of ribonucleotide reductase.
E. PRPP to phosphoribosylamine:
o This reaction is catalyzed by glutamine PRPP amidotransferase, the rate-limiting enzyme of de novo purine synthesis. It is not a target of hydroxyurea.
Key Takeaway:
Hydroxyurea inhibits ribonucleotide reductase, reducing the conversion of ribonucleotides (e.g., ADP) to deoxyribonucleotides (e.g., dADP), which are essential for DNA synthesis. This mechanism is particularly effective in targeting rapidly dividing cancer cells.
25 . Which of the following best describes the role of glutamine PRPP amidotransferase in nucleotide metabolism?
A. It is an enzyme involved in de novo pyrimidine nucleotide biosynthesis.
B. It is activated by PRPP and inhibited by AMP and GMP.
C. It is activated by UTP and inhibited by PRPP.
D. It is activated by GMP and inhibited by CTP.
E. It is an enzyme of the nucleotide salvage pathway.
Correct Answer: B. It is activated by PRPP and inhibited by AMP and GMP.
Explanation:
• Glutamine PRPP amidotransferase is a key regulatory enzyme in the de novo purine nucleotide biosynthesis pathway.
• It catalyzes the first committed step in purine synthesis, converting PRPP (phosphoribosyl pyrophosphate) and glutamine into 5-phosphoribosylamine, an early precursor for purine nucleotides.
• Regulation:
o Activated by PRPP: High levels of PRPP stimulate the enzyme, signaling the need for purine synthesis.
o Inhibited by AMP and GMP: These purine end products act as feedback inhibitors, reducing enzyme activity to maintain nucleotide balance.
Incorrect Options:
A. It is an enzyme involved in de novo pyrimidine nucleotide biosynthesis:
o This is incorrect because glutamine PRPP amidotransferase functions in the purine nucleotide biosynthesis pathway, not pyrimidine synthesis.
C. It is activated by UTP and inhibited by PRPP:
o UTP regulates pyrimidine biosynthesis, not purine biosynthesis. PRPP activates this enzyme, not inhibits it.
D. It is activated by GMP and inhibited by CTP:
o GMP inhibits this enzyme as part of feedback regulation. CTP is involved in pyrimidine metabolism and does not regulate this enzyme.
E. It is an enzyme of the nucleotide salvage pathway:
o This is incorrect because this enzyme is part of the de novo pathway, not the salvage pathway. The salvage pathway involves enzymes like HGPRT and APRT.
