Lecture notes study book Harper's Illustrated Biochemistry Thirty-First Edition of Victor Rodwell, David Bender - ISBN: 9781259837944, Edition: 31, Year of publication: - (medicine notes)
Biomedical importance:
a. energy metabolism, protein synthesis, regulation of enzyme activity, signal transduction
b. prinicipal donors and acceptors of phosphoryl groups in metabolism
c. nucleoside tri- and diphosphates (ATP, ADP) – energy transduction with metabolic interconversions and oxidative phosphorylation
d. form a portion of coenzymes with vitamins / vitamin derivatives
e. nucleosides linked to sugars or lipids -> key biosynthetic intermediates
f. UDP-glucose, UDP-galactose – sugar interconversions in biosynthesis of starch and glycogen
g. CDP-acylglycerol (nucleoside-lipid derivatives) – intermediates in biosynthesis
h. Metabolic regulation:
a. ATP-dependent phosphorylation by key metabolic enzymes
b. Allosteric regulation by ATP, AMP, CTP and control by ADP of rate of oxidative phosphorylation
i. Second messengers in hormonally regulated events: cyclic cAMP, cGMP
j. Signal transduction pathways: GTP, GDP
Heterocyclic compounds
- nitrogen containing (other than C)
- rings numbered in opposite directions (Pu – right; Py – left)
- planar – close association or “stacking” – stabilizes DNA
- oxo and amino groups of Pu and Py exhibit keto-enol and amine-imine tautomerism
Tautomerism – permitting some compounds to ‘switch’
Isomers = interconversible at equilibrium
- formal migration
- switch of single bond to double bond
1. Components of nucleoside & nucleotide
1.1. Types of bonds
1.1.1. Glycosidic bond
- nucleosides – derivatives of Pu and Py that have sugar linked to ring nitrogen
- (sugar)
o ribonucleosides – D-ribose
o deoxyribonucleosides – 2-deoxy-D-ribose
✓ linked to the heterocycle: B-N-glycosidic bond
▪ to the N-1 of pyrimidine; N-9 of purine
▪ steric hindrance (by the heterocycle) – no freedom of rotation about the bond – both (nucleosides or nucleotides)
therefore exist as syn or anti conformers – noninterconvertible; only interconverted by cleavage and reformation of the
glycosidic bond
1.1.2. Acid anhydride bond
- ligates additional phosphoryl groups to phosphoryl group of a mononucleotide = form nucleoside diphosphates and triphosphates
- high energy
Mononucleotides – nucleosides with phosphoryl group esterified to a hydroxyl group
- 3’- and 5’- nucleotides – with phosphoryl group in 3’- or 5’- hydroxyl group
- C5 – UMP, dAMP
*nucleosides and nucleotides - Syn or anti conformers – noniconvertible
- only inconverted by cleavage and reformation of the glycosidic bond
2. Few minor or modified bases and its significance
Modification – can generate additional structures
- 5-methylcytosine5-methylcytosine in bacterial and human DNA
- 5-hydroxymethylcytosine of bacterial and viral nucleic acids
- mono- and di-N-methylated adenine, guanine of mRNA – oligonucleotide recognition in regulating half-lives of RNA
- free nucleotides: hypoxanthine, xanthine, uric acid – intermediates in catabolism of adenine, guanine
- methylated hetercycles of plants: xanthine derivatives (coffee) [1, 3, 7 C atom], theophylline (tea), theobromine (cocoa) [3, 7 C atom]
Polynucleotides – DNA, RNA
- phosphodiester – can be formed by esterification of second hydroxyl group by 5’-phosphoryl group of mononucleotide
- 2nd hydroxyl is 3’-OH of pentose of 2nd nucleotide -> dinucleotide (pentose moieties linked by 3’,5’-phosphodiester bond – backbone of RNA, DNA)
, - Dinucleotide – elimination of H2O between 2 mononucleotides
- No biologic formation; hydrolysis is strongly favored on thermodynmic grounds
- In absence of catalysis by phosphodiesterases, hydrolysis of phosphodiester bonds of DNA occur over long periods of time
- Posttranslational modification -> additional structures
o Pseudouridine – D-ribose is linked to C5 of uracil by a carbon to carbon bond (usual β-N-glycosidic bond)
o Pseudouridylic acid – rearrangement of a UMP of a performed tRNA
o TMP (thymidine monophosphate) – methylation by S-adenosylmethionine of a UMP; contains ribose rather than deoxyribose
- Directional macromolecules
- 5’-end – free / phosphorylated 5’-hydroxyl
3. Name / enumerate the physicochemical properties of purine and pyrimidine bases and their relevance
3.1. Predominant tautomer of each base -> oxo & amino (favored by physiologic conditions)
3.2. uV absorption spectrum of base, nucleoside, nucleotide
- conjugated double bonds absorb uV light
- mutagenic effect – d/t absorption by nucleotides in DNA
- spectra – pH dependent
- pH 7.0 – all common NT absorb light at wavelength of 260nm = “absorbance at 260nm”
3.3. Differentiate solubility of uric acid from urate at neutral pH and lower pH
- depends on acidity of environment
- urates:
o seen in acidic pH >5.5
o soluble with alkali and heat
o normal in urine
- uric acid:
o seen in acidic pH <5.5
o soluble in alkali only
o if above normal value, indicates hyperuricemia
4. Differentiate ribonucleotide & deoxyribonucleotide as to:
5. Enumerate different metabolic functions of naturally occurring nucleotides
5.1. Specific nucleotide involved
- ATP – principal biologic transducer of free energy; second messenger of cAMP
o Most abundant free nucleotide
o Mean intracellular concentration = 1mmol/L
* cAMP concentration = 2nmol/L
Precursors of nucleic acids:
- Adenosine 3’-phosphate-5’phosphosulfate – sulfate donor for sulfated proteoglycans; for sulfate conjugates of drugs
- S-adenosylmethionine – methyl group donor
- GTP – allosteric regulator; energy for protein synthesis
- cGMP – 2nd messenger in response to nitric oxide during relaxation of smooth muscle; binding of hormones to ligands
- UDP-sugar derivatives – sugar epimerization; biosynthesis of glycogen, glucosyl disaccharides, oligosaccharides of glycoproteins and proteoglycans
- UDP-glucuronic acid – forms urinary glucuronide conjugates of bilirubin and of many drugs (eg aspirin)
- CTP – biosynthesis of phosphoglycerides, sphingomyelin and other sphingosines
5.2. Relate its function to its structural feature
- high group transfer potential – acid anhydrides
- purine and pyrimidine nucleoside triphosphates -> function as group transfer reagents (most freq of the γ-phosphoryl
group)
- cleavage – acid anhydride bond
– coupled with a highly endergonic process
▪ covalent bond synthesis – eg polymerization of nucleoside triphosphates to form nucleic acid
endergonic – absorbs heat
exergonic – release heat; in hydrolysis of ATP
6. Identify and / or name some synthetic nucleoside, nucleotide analogs -> antimetabolites (chemotherapeutic agents)
6.1. Name its two general mechanisms of action
- Toxic effects:
o Inhibition of enzyme for nucleic acid synthesis or
o Incorporation into nucleic acids with resulting disruption of base-pairing; substitutes purine and pyrimidine
- Incorporated into DNA prior to cell division:
o 5-fluoro or 5-iodouracil
o 3-deoxyuridine
o 6-thioguanine
o 6-mercaptopurine
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