Increased bilirubin production and conjugation occurs with hemolysis. The conjugated bilirubin is sent to the intestine where it is converted to urobilinogen. Some urobilinogen is reabsorbed and enters the portal blood, traveling to the kidney. In obstructive jaundice, the common bile duct obstruction leads to low intestinal urobilinogen levels, resulting in low urinary urobilinogen. Obstructive jaundice is depicted in Figure D.

Case 7: Gout and Joint Pain

Answer = F. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) facilitates the conversion of the purine bases hypoxanthine and guanine to inosine monophosphate (IMP) and guanosine monophosphate (GMP), respectively. This process requires 5-phosphoribosyl-1-pyrophosphate (PRPP) as the source of ribose 1-phosphate. Salvage of purine bases reduces the substrate available for degradation to uric acid. Therefore, a deficiency in salvage leads to hyperuricemia, as shown in the figure on the right. Oxypurinol, a noncompetitive inhibitor, affects the apparent maximal velocity (Vmax) but not the Michaelis constant (Km).

Colchicine is an anti-inflammatory drug that does not affect purine synthesis or degradation enzymes. Glutamine, not glutamate, serves as a nitrogen source for purine ring synthesis. In purine nucleotide synthesis, the purine ring system is built on ribose 5-phosphate provided by PRPP. Allopurinol and its metabolite, oxypurinol, inhibit xanthine oxidase involved in purine degradation. The regulated enzyme of purine synthesis is the amidotransferase, which is inhibited by purine nucleotides and stimulated by PRPP.

Answer = B. Methotrexate inhibits dihydrofolate reductase, reducing the availability of N5,N10-methylene tetrahydrofolate required for the synthesis of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) by thymidylate synthase. Carbamoyl phosphate synthetase (CPS) II is the regulated enzymic activity involved in pyrimidine biosynthesis in humans. CPS I is an enzyme of the urea cycle. Orotic aciduria, a rare disorder of pyrimidine synthesis, occurs due to a deficiency in one or both enzymic activities of bifunctional uridine monophosphate synthase. PRPP is essential for pyrimidine nucleotide synthesis, similar to purine synthesis and salvage.

Increased PRPP synthetase activity leads to increased PRPP synthesis, resulting in excessive purine nucleotide synthesis. The excess purine nucleotides are degraded to uric acid, causing hyperuricemia.

Case 8: Cystic Fibrosis and No Bowel Movement
With hemolysis, more bilirubin is produced and conjugated. CB is sent to the intestine where it is converted to urobilinogen, some of which is reabsorbed, enters the portal blood, and travels to the kidney. Because the source of urinary urobilinogen is intestinal urobilinogen, urinary urobilinogen will be low in obstructive jaundice because intestinal urobilinogen will be low as a result of the obstruction of the common bile duct (see Figure D).
Case 7: Joint Pain with Gout
Answer = F. Salvage of the purine bases hypoxanthine and guanine to the purine nucleotides inosine monophosphate (IMP) and guanosine monophosphate (GMP) by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) requires 5-phosphoribosyl-1-pyrophosphate (PRPP) as the source of the ribose 1phosphate. Salvage decreases the amount of substrate available for degradation to uric acid. Therefore, a deficiency in salvage results in hyperuricemia (see figure at right). Noncompetitive inhibitors such as oxypurinol have no effect on the Michaelis constant (Km) but decrease the apparent maximal velocity (Vmax).
Colchicine is an anti-inflammatory drug. It has no effect on the enzymes of purine synthesis or degradation. Glutamine (not glutamate) is a nitrogen source for purine ring synthesis. In purine nucleotide synthesis, the purine ring system is constructed on the ribose 5-phosphate provided by PRPP. Allopurinol and its metabolite, oxypurinol, inhibit xanthine oxidase of purine degradation. The amidotransferase is the regulated enzyme of purine synthesis. Its activity is decreased by purine nucleotides and increased by PRPP.
Answer = B. Methotrexate inhibits dihydrofolate reductase, decreasing the availability of N5,N10-methylene tetrahydrofolate needed for synthesis of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) by thymidylate synthase (see figure at right). Carbamoyl phosphate synthetase (CPS) II is the regulated enzymic activity of pyrimidine biosynthesis in humans. CPS I is an enzyme of the urea cycle. Orotic aciduria is a rare pathology of pyrimidine synthesis caused by a deficiency in one or both enzymic activities of bifunctional uridine monophosphate synthase. Pyrimidine nucleotide synthesis, like purine synthesis and salvage, requires PRPP.
Increased activity of PRPP synthetase results in increased synthesis of PRPP. This results in an increase in purine nucleotide synthesis beyond need. The excess purine nucleotides get degraded to uric acid, thereby causing hyperuricemia.
Case 8: No Bowel Movement with Cystic Fibrosis