Updated: 3/23/2018

De Novo Nucleotide Synthesis

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Overview
  • Phosphoribosyl pyrophosphate (PRPP)
    • sugar building block formed in nucleotide synthesis
      • added to nitrogenous base to form nucleoside
    • formed from ribose-5-phosphate
      • product of pentose phosphate shunt
    • ATP + ribose-5-phosphate = PRPP + AMP
      • catalyzed by PRPP synthetase
    • once PRPP is made it can add to either a de novo or salvaged base
  • Pyrimidine 
    • pathway diagram
    • important enzymes
      • carbamoyl phosphate synthetase-2
        • rate limiting step
        • not the same carbamoyl phosphate as in urea cycle
      • ribonucleotide reductase
        • inhibited by hydroxyurea 
        • also reduces UDP, CDP, ADP, GDP
          • dADP and dATP negatively feedback and inhibit enzyme
        • result = ↓ dTMP, dUDP, dCDP, dADP, dGDP
          • note: good to target thymidine synthesis because it is not involved in RNA
      • thymidylate synthase
        • inhibited by 5-fluorouracil (5-FU)
        • result = ↓ dTMP
      • dihydrofolate reductase
        • inhibited by methotrexate (MTX) in eukaryotes
        • inhibited by trimethoprim (TMP) in prokaryotes
          • sulfamethoxazole (SMX) interferes with DHF synthesis in prokaryotes
          • co-trimoxazole = TMP + SMX
        • inhibited by pyrimethamine in protozoa
        • result = ↓ dTMP
    • deficiency
      • orotic aciduria 
        • inability to convert orotic acid to UMP
        • defect in uridine monophosphate (UMP) synthase 
        • AR
        • presentation
          • ↑ orotic acid crystals in urine
          • megaloblastic anemia
            • does not improve with administration of vitamin B12 or folic acid
            • not enough thymidine to sustain normal erythropoiesis
          • failure to thrive
          • no hyperammonemia
            • distinguishes between ornithine transcarbamylase (OTC) deficiency with high [orotic acid] in urine with hyperammonemia
        • treatment
          • oral uridine administration
            • bypasses defect in de novo pyrimidine pathway 
  • purine 
    • pathway diagram
    • insufficient capacity in most cells
    • important enzymes
      • PRPP amidotransferase
        • rate-limiting step
        • inhibited by AMP, GMP, IMP
        • indirectly inhibited by allopurinol
        • indirectly inhibited by 6-mercaptopurine
    • note: base of inosine = hypoxanthine
 

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Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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(M1.BC.6237) A 9-month-old female infant presents with failure to thrive, repeated respiratory infections, and anemia refractory to administration of cobalamin, pyridoxine, folic acid, and iron (Figure A). Urinalysis demonstrates a crystalline sediment and a blood test shows normal ammonia levels. Which of the following enzymes is defective in this infant? Review Topic

QID: 106239
FIGURES:
1

Ornithine transcarbamoylase

20%

(56/280)

2

Adenosine deaminase

19%

(52/280)

3

Hypoxanthine-guanine phosphoribosyltransferase

10%

(29/280)

4

Xanthine oxidase

8%

(22/280)

5

UMP synthase

42%

(117/280)

M1

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PREFERRED RESPONSE 5
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(M1.BC.4707) A 12-year-old African American female presents to the emergency department with acute chest pain and swelling of hands and feet after running with her friends. She has previously had numerous episodes of fatigue and bone pain and a family history shows several relatives with anemia. A peripheral blood smear is performed and the results are shown in the photograph (Figure A). After confirmation of the diagnosis, she is prescribed a drug that is designed to alleviate the disorder by increasing the level of circulating fetal hemoglobin. Which of the following enzymes is affected by the medication that was most likely prescribed in this case? Review Topic

QID: 108427
FIGURES:
1

Dihydrofolate reductase

26%

(57/217)

2

Inosine monophosphate (IMP) dehydrogenase

12%

(25/217)

3

Methionine synthase

9%

(19/217)

4

Pyruvate kinase

12%

(26/217)

5

Ribonucleotide reductase

37%

(80/217)

M1

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PREFERRED RESPONSE 5
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