p.10
Drug Inhibition of Nucleotide Biosynthesis
How do sulfonamide drugs work?
They competitively inhibit dihydropteroate synthase to decrease folic acid synthesis in bacteria.
p.12
Gout and Hyperuricemia
What is the primary cause of hyperuricemia in over 90% of individuals?
Underexcretion of uric acid.
p.12
Gout and Hyperuricemia
What is a less common cause of hyperuricemia?
Overproduction of uric acid.
p.12
Gout and Hyperuricemia
What genetic mutation is associated with increased purine synthesis leading to hyperuricemia?
X-linked PRPP synthetase overactivity mutations.
p.9
Synthesis of Deoxyribonucleotides
What are the nucleotides required for DNA synthesis?
2’-deoxy ribonucleotides (dNTPs).
p.4
Endogenous Purine Biosynthesis and Salvage Pathways
What is produced at the end of the nine reactions following the committed step?
Inosine monophosphate (IMP).
p.2
Nucleotide Structure and Components
What is produced by adding 1, 2, or 3 phosphate groups to the 5’-OH of a pentose sugar?
A nucleotide or nucleoside phosphate (mono-, di-, or tri-phosphate).
p.3
Endogenous Purine Biosynthesis and Salvage Pathways
What is the effect of negative allosteric effects?
They decrease the binding affinity of the enzyme to its substrate.
p.14
Drug Inhibition of Nucleotide Biosynthesis
How does Allopurinol work biochemically?
It is converted to oxypurinol, which competitively inhibits xanthine oxidase, decreasing uric acid synthesis.
p.13
Gout and Hyperuricemia
What dietary factors can increase gout incidence?
Purine-rich foods such as fish, red meat, and beer.
p.1
Nucleotide Structure and Components
What are the components of a nucleotide?
A nitrogenous base, a pentose monosaccharide (sugar), and 1-3 phosphate groups.
p.11
Gout and Hyperuricemia
What is GOUT characterized by?
Chronic hyperuricemia with intermittent acute attacks of inflammation or chronic arthritis.
p.15
Clinical Management of Gout
What is Pegloticase used for?
It is recently approved for long-term treatment of gout.
p.10
Drug Inhibition of Nucleotide Biosynthesis
What type of drugs inhibit folate synthesis in bacteria?
Antibiotics, such as sulfonamide drugs and trimethoprim.
p.10
Clinical Management of Gout
What are the potential side effects of methotrexate?
Hair loss, nausea, and vomiting due to toxicity in rapidly dividing normal cells.
p.15
Clinical Management of Gout
What is Rasburicase commonly used for?
It is often used for the prevention of tumor lysis syndrome.
p.6
Endogenous Purine Biosynthesis and Salvage Pathways
What is the role of IMP in purine biosynthesis?
IMP is a branch point that can be converted to either AMP or GMP as needed.
p.6
Endogenous Purine Biosynthesis and Salvage Pathways
How do AMP and GMP regulate purine levels?
As end-product inhibitors, they can inhibit their own synthesis and influence the conversion of IMP.
p.9
Pyrimidine Synthesis and Regulation
What is the role of nucleoside kinases in pyrimidine salvage?
They phosphorylate nucleosides to nucleotides using ATP as an energy source.
p.6
Endogenous Purine Biosynthesis and Salvage Pathways
Why is the salvage pathway advantageous compared to de novo synthesis?
It requires less energy expenditure.
p.12
Gout and Hyperuricemia
What happens during an acute gout attack?
Inflammation occurs in the joint, causing swelling, warmth, redness, and tenderness.
p.12
Gout and Hyperuricemia
How often do acute gout attacks typically occur?
1-2 times per year and often affect only one joint.
p.3
Endogenous Purine Biosynthesis and Salvage Pathways
What is the effect of positive allosteric effects?
They increase the binding affinity of the enzyme to its substrate.
p.14
Drug Inhibition of Nucleotide Biosynthesis
What is the role of Allopurinol in gout treatment?
It inhibits uric acid synthesis and is effective in reducing SUA levels in both overproducers and underexcretors.
p.2
Catabolism of Pyrimidines and Purines
What happens to most purines after digestion?
They are converted to uric acid, which enters the blood and is excreted by the kidneys.
p.13
Clinical Management of Gout
What are some anti-inflammatory agents used during an acute gout attack?
Indomethacin, NSAIDs, steroids (e.g., prednisone), and colchicine.
p.11
Catabolism of Pyrimidines and Purines
What is the role of 5’ Nucleotidase in purine degradation?
Converts IMP and GMP to their nucleoside forms.
p.10
Drug Inhibition of Nucleotide Biosynthesis
What is the role of methotrexate in cancer treatment?
It competitively inhibits DHF reductase, depleting THF and inhibiting nucleotide synthesis in human cells.
p.6
Endogenous Purine Biosynthesis and Salvage Pathways
What happens when there is excess AMP?
It inhibits its own synthesis, leading to more IMP being converted to GMP.
p.10
Drug Inhibition of Nucleotide Biosynthesis
What is mycophenolic acid used for?
It is an immunosuppressant used in organ transplants to prevent graft rejection.
p.4
Endogenous Purine Biosynthesis and Salvage Pathways
What do AMP and GMP purine nucleotides act as when purine levels are adequate?
End-product inhibitors (negative allosteric effectors).
p.3
Endogenous Purine Biosynthesis and Salvage Pathways
What is required for the de novo construction of the purine ring?
ATP for energy and the stepwise addition of individual atoms from amino acids, CO2, and N10-formyltetrahydrofolate.
p.12
Gout and Hyperuricemia
When do acute gout attacks typically occur?
Suddenly at night or early morning under conditions favoring decreased solubility of uric acid.
p.14
Clinical Management of Gout
When is urate-lowering therapy (ULT) initiated?
If SUA is still greater than approximately 7 mg/dL after managing the acute attack.
p.13
Gout and Hyperuricemia
What leads to chronic tophaceous gout?
Hyperuricemia causing accumulation of MSU crystals, resulting in multiple severe attacks.
p.7
Endogenous Purine Biosynthesis and Salvage Pathways
What does Adenine phosphoribosyltransferase (APRT) convert?
It converts Adenine to AMP irreversibly.
p.7
Gout and Hyperuricemia
What are the symptoms of excessive purine production in Lesch-Nyhan syndrome?
Formation of uric acid stones, gouty arthritis, motor dysfunction, cognitive deficits, and behavioral disturbances.
p.7
Pyrimidine Synthesis and Regulation
What enzyme catalyzes the production of carbamoyl phosphate?
Carbamoyl phosphate synthetase (CPS) II.
p.11
Catabolism of Pyrimidines and Purines
What genetic deficiencies can cause depletion of lymphocytes?
Deficiencies of ADA and PNP.
p.16
Clinical Management of Gout
What is the first step in managing an acute attack of gout?
Reducing pain and inflammation by administering Indomethacin.
p.8
Pyrimidine Synthesis and Regulation
What is the product of adding PRPP to orotic acid?
Uridine 5’-monophosphate (UMP).
p.3
Endogenous Purine Biosynthesis and Salvage Pathways
Which amino acids are involved in purine ring biosynthesis?
Aspartate (Asp), Glycine (Gly), and Glutamine (Gln).
p.13
Clinical Management of Gout
What is podagra?
A condition where 50% of gout attacks affect the first metatarsophalangeal joint of the big toe.
p.13
Gout and Hyperuricemia
What is urolithiasis?
Formation of uric acid stones in the kidney.
p.13
Gout and Hyperuricemia
What factors influence the incidence of gout?
Age, sex, diet, overweight/obesity, and certain drugs.
p.1
Roles of Nucleotides in Human Cells
What is the 'energy currency' of the cell?
ATP (adenosine triphosphate).
p.1
Roles of Nucleotides in Human Cells
What role do nucleotides play in carbohydrate synthesis?
Nucleotides act as carriers of activated intermediates, such as UDP-glucose in glycogen synthesis.
p.11
Catabolism of Pyrimidines and Purines
What does purine nucleoside phosphorylase (PNP) convert Inosine and Guanosine to?
Hypoxanthine and Guanine, respectively.
p.10
Drug Inhibition of Nucleotide Biosynthesis
What is the mechanism of action of 5-fluorouracil?
It inhibits thymidylate synthase during thymidine nucleotide synthesis as a 'suicide' inhibitor.
p.4
Endogenous Purine Biosynthesis and Salvage Pathways
What activates Glutamine:PRPP amidotransferase (GPAT)?
PRPP (5-phosphoribosyl-1-pyrophosphate).
p.3
Endogenous Purine Biosynthesis and Salvage Pathways
What is the role of PRPP in purine biosynthesis?
PRPP is the 'activated' ribose 5-phosphate donor for both purine biosynthesis and salvage, as well as pyrimidine biosynthesis.
p.3
Endogenous Purine Biosynthesis and Salvage Pathways
How is PRPP synthetase regulated?
It is activated by inorganic phosphate (Pi) and ATP, and regulated through end-product inhibition by purine nucleotide end-products.
p.2
Nucleotide Structure and Components
What are deoxyribonucleotides?
Deoxyribonucleoside triphosphates such as dATP, dGTP, dCTP, and dTTP.
p.2
Digestion and Nutritional Impact on Nucleotide Metabolism
How are dietary nucleic acids digested?
They are denatured in the stomach and digested in the small intestine by pancreatic enzymes.
p.2
Endogenous Purine Biosynthesis and Salvage Pathways
What is the salvage mechanism in purine biosynthesis?
It allows purine nucleotides to be produced with lower energy requirements using de novo synthesized bases and nucleosides from the liver.
p.13
Clinical Management of Gout
What should be done during the intercritical period of gout?
Lower SUA levels using uric acid lowering therapy (UALT) approaches.
p.12
Gout and Hyperuricemia
What are some factors that can cause underexcretion of uric acid?
Kidney disease, age-related decrease in kidney filtration rate, heart disease, genetic predisposition, and environmental factors.
p.4
Endogenous Purine Biosynthesis and Salvage Pathways
What is the committed, regulatory step in purine synthesis?
Synthesis of 5’-phosphoribosylamine.
p.10
Catabolism of Pyrimidines and Purines
What are the products of pyrimidine catabolism?
β-alanine, β-aminoisobutyrate, NH3, and CO2.
p.12
Gout and Hyperuricemia
What syndrome causes excessive de novo purine production?
Lesch-Nyhan syndrome (LNS).
p.9
Synthesis of Deoxyribonucleotides
What does ribonucleotide reductase do?
It reduces the 2’-OH group of NDPs to produce dNDPs using NADPH.
p.8
Pyrimidine Synthesis and Regulation
What are the symptoms of orotic aciduria?
Failure to thrive and megaloblastic anemia.
p.8
Pyrimidine Synthesis and Regulation
How is UMP converted to UTP?
Through a series of kinase reactions.
p.14
Drug Inhibition of Nucleotide Biosynthesis
Name two uricosuric agents.
Probenecid and Sulfinpyrazone.
p.13
Clinical Management of Gout
How is gout definitively diagnosed?
By visualizing needle-shaped monosodium urate crystals in synovial fluid using light microscopy.
p.13
Clinical Management of Gout
What should be managed during an acute gout attack?
Pain and inflammation, without attempting to lower SUA levels.
p.1
Nucleotide Structure and Components
What distinguishes a nucleoside from a nucleotide?
A nucleoside consists of a pentose sugar and a base, while a nucleotide includes a pentose sugar, a base, and one or more phosphate groups.
p.1
Nucleotide Structure and Components
What types of sugars are found in ribonucleosides and deoxyribonucleosides?
Ribonucleosides contain ribose sugar, while deoxyribonucleosides contain 2-deoxyribose sugar.
p.15
Drug Inhibition of Nucleotide Biosynthesis
What is the function of recombinant urate oxidase/uricase?
It converts uric acid to allantoin, which is more soluble.
p.10
Synthesis of Deoxyribonucleotides
What is required for nucleic acid synthesis and cell division?
An adequate supply of nucleotides.
p.10
Drug Inhibition of Nucleotide Biosynthesis
What does hydroxyurea do?
It depletes cellular dNTP levels required for cell division by inhibiting ribonucleotide reductase.
p.9
Synthesis of Deoxyribonucleotides
What is the pathway for thymidine deoxynucleotides synthesis?
UMP, dCTP or dCMP → dUMP → dTMP → dTTP.
p.13
Gout and Hyperuricemia
What is a tophus?
A mass comprised of MSU crystals that forms in soft tissues, often in extremities.
p.14
Drug Inhibition of Nucleotide Biosynthesis
What is Febuxostat and how does it differ from Allopurinol?
Febuxostat is a non-purine inhibitor of xanthine oxidase that non-competitively blocks the enzyme’s active site; it may be more effective in some patients than Allopurinol.
p.1
Roles of Nucleotides in Human Cells
What are the essential roles of nucleotides in human cells?
Nucleotides are essential for energy currency (ATP), production of RNA and DNA, carriers of activated intermediates, second messengers in signal transduction, and enzyme regulation.
p.7
Pyrimidine Synthesis and Regulation
What inhibits CPS II activity?
UTP via end-product inhibition.
p.15
Gout and Hyperuricemia
Why might individuals undergoing chemotherapy develop hyperuricemia?
Due to high levels of cell death and subsequent increase in availability of nucleotides.
p.16
Synthesis of Deoxyribonucleotides
What enzyme is required for the conversion of ribonucleotides to deoxyribonucleotides?
Ribonucleotide reductase.
p.12
Gout and Hyperuricemia
What clinical symptoms occur when serum uric acid (SUA) levels exceed 6.8 mg/dL?
Localized inflammatory response and formation of monosodium urate (MSU) crystals.
p.14
Clinical Management of Gout
What is the intercritical period in gout management?
The asymptomatic period of approximately 2 weeks following an acute gout attack.
p.9
Drug Inhibition of Nucleotide Biosynthesis
What role do folate and its derivatives play in nucleotide biosynthesis?
They are one-carbon donors and coenzymes in many enzymatic reactions.
p.14
Drug Inhibition of Nucleotide Biosynthesis
What is the mechanism of uricosuric agents?
They competitively inhibit reabsorption of uric acid by kidney tubules, increasing its excretion in urine.
p.2
Digestion and Nutritional Impact on Nucleotide Metabolism
What types of foods are rich in nucleotides?
Offal, red meat, poultry, seafood, yeast, mushrooms, and non-distilled alcoholic beverages, especially beer.
p.2
Endogenous Purine Biosynthesis and Salvage Pathways
What is the primary site of de novo purine biosynthesis?
The cytoplasm of liver hepatocytes.
p.13
Clinical Management of Gout
What is the role of colchicine in gout treatment?
It reduces gout-induced inflammation by preventing microtubule formation.
p.1
Roles of Nucleotides in Human Cells
What are second messengers in signal transduction pathways?
cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate).
p.6
Endogenous Purine Biosynthesis and Salvage Pathways
What regulates the conversion of NMPs to NDPs and NTPs?
Base-specific and general nucleoside kinases.
p.9
Synthesis of Deoxyribonucleotides
How are dNTPs produced?
From ribonucleoside diphosphates (NDPs) via ribonucleotide reductase during S-phase of the cell cycle.
p.4
Endogenous Purine Biosynthesis and Salvage Pathways
What components are added to ribose-5-phosphate to build the purine ring structure?
Carbon and Nitrogen atoms from Gln, Gly, and Asp amino acids.
p.4
Endogenous Purine Biosynthesis and Salvage Pathways
What derivative is required in two steps of purine synthesis?
N10-formyltetrahydrofolate (folic acid derivative).
p.14
Clinical Management of Gout
What can cause flare-ups during SUA level lowering?
Resolubilization of monosodium urate crystals can cause episodic SUA elevations.
p.2
Digestion and Nutritional Impact on Nucleotide Metabolism
What is required for normal nucleotide synthesis?
Adequate protein/amino acid and vitamin intake (e.g., folic acid).
p.7
Gout and Hyperuricemia
What is Lesch-Nyhan syndrome associated with?
Impaired purine salvage due to HGPRT deficiency.
p.7
Pyrimidine Synthesis and Regulation
How is pyrimidine synthesis different from purine synthesis?
The pyrimidine base is synthesized before ribose 5-phosphate is attached.
p.1
Nucleotide Structure and Components
What are the nitrogenous bases found in RNA and DNA?
DNA contains A, G, C, and T; RNA contains A, G, C, and U (uracil replaces thymine).
p.11
Catabolism of Pyrimidines and Purines
What does adenosine deaminase (ADA) convert AMP to?
IMP or Adenosine to Inosine.
p.6
Endogenous Purine Biosynthesis and Salvage Pathways
What happens when there is excess GMP?
It inhibits its own synthesis, leading to more IMP being converted to AMP.
p.9
Pyrimidine Synthesis and Regulation
What is the significance of uridine salvage to UTP?
It is responsible for the effectiveness of uridine as a treatment for orotic aciduria.
p.6
Endogenous Purine Biosynthesis and Salvage Pathways
What is the purine salvage pathway?
A process that reutilizes free purine bases derived from nucleic acids to convert them into nucleoside triphosphates.
p.9
Synthesis of Deoxyribonucleotides
How does ATP affect ribonucleotide reductase?
ATP activates it, while dATP inhibits it.
p.8
Pyrimidine Synthesis and Regulation
What is the treatment for orotic aciduria?
Administration of exogenous uridine nucleoside.
p.8
Pyrimidine Synthesis and Regulation
What does CTP synthetase do?
Converts UTP to CTP by adding an amino group from glutamine.
p.2
Nucleotide Structure and Components
What are ribonucleotides?
Ribonucleoside triphosphates such as ATP, GTP, CTP, and UTP.
p.7
Endogenous Purine Biosynthesis and Salvage Pathways
What is the function of Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)?
It catalyzes the irreversible conversion of Hypoxanthine to IMP and Guanine to GMP.
p.7
Gout and Hyperuricemia
What are the consequences of HGPRT deficiency?
Increased PRPP levels and decreased IMP and GMP levels, leading to excessive de novo purine production.
p.7
Pyrimidine Synthesis and Regulation
What is the committed regulatory step of the pyrimidine biosynthetic pathway?
Synthesis of carbamoyl phosphate.
p.1
Roles of Nucleotides in Human Cells
What are some examples of important coenzymes that nucleotides are components of?
Coenzyme A, FAD, NAD+, and NADP+.
p.11
Catabolism of Pyrimidines and Purines
What is the function of xanthine oxidase (XO) in purine catabolism?
Oxidizes Hypoxanthine to Xanthine and then to uric acid.
