Biochemistry: Nucleotides, Xanthines, Cancer Drugs, Gout
Nucleic acid = polymer of nucleotide, ex: DNA, FNA
nucleotide = a pentose sugar + nitrogenous base + phosphate(s)
nucleoside = sugar + base (no phosphates)
nitrogenous base = a one or two ring structure with several nitrogens in it, two types: purines & pyrimidines
PURINES = the two ring bases, adenine & guanine are part of DNA & RNA, there are also purines in coffee (caffeine), tea (theophylline) and cocoa (theobromine).
caffeine = trimethyl xanthine = 1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione = psychoactive stimulant drug (unregulated) and mild diuretic = also called guaranine when found in guarana, mateine when found in mate, and theine when found in tea; all of these names are synonyms for the same chemical compound (???)
theophylline = dimethyl xanthine = a drug used in therapy for respiratory diseases such as COPD or asthma. Due to its numerous side-effects, these drugs are now rarely administered for clinical use. Naturally found in tea, although in trace quantities (~1 mg/L),[1] significantly less than therapeutic doses. Actions: relaxing bronchial smooth muscle, increasing heart muscle contractility and efficiency: positive inotropic, increasing heart rate: positive chronotropic, increasing blood pressure, increasing renal blood flow, some anti-inflammatory effects, central nervous system stimulatory effect mainly on the medullary respiratory center.
theobromine = xantheose = bitter alkaloid of the cacao plant, found in chocolate
--in the methylxanthine class of chemical compounds, which incl theophylline and caffeine
--contains no bromine -name derived from Theobroma, the name of the genus of the cacao tree (Greek roots: theo=God and brosi=food)
--suffix -ine given to alkaloids and other basic nitrogen-containing compounds
--water insoluble, crystalline, bitter
--similar but lesser effect to caffeine
xanthine = product of purine degradation
CANCER DRUGS
--often target purine synthesis and recycling
--limit cell division to slow down fast growing tumors (neoplasms)
--5-FLOUROURACIL is a uracil analog that blocks formation of fDUMP by inhibiting thymidylate synthase
--METHOTREXATE is a folic acid analog that blocks regeneration of THF
--methotrexate inhibits synthesis of deoxythymidine monophosphate
--methotrexate inhibits function of dyhydrofolate reductase --> less THF
Purine synthesis begins with making PRPP. It starts with a phosphorylated pentose sugar, and the rate limiting step uses PPRP synthetase and converts and ATP to an AMP. PPRP has 2 phosphates and the purine base is built onto it. The atoms of the two ring purine base come from: aspartate (1 nitrogen), CO2 (1 carbon), glycine (1 nitrogen 2 carbons), THF (1 carbon), glutamine (2 nitrogens), TH4 (1 carbon). The THF carbons come from serine, histidine, or other aa's.
PURINE HIGH POINTS:
--location: liver cytosol
--liver exports nucleosides and free bases
--sources of atoms for rings: aspartate, Co2, glycine, TH4, glutamine
--Nitrogen from: glycine, glutamine, aspartate
--Carbon from: Co2, THF, glycine
--Whole glycine incorporated
--THF = tetrahydrofolate = does one carbon transfers = need FOLATE in diet
--PPRP = 5-phosphoribosyl 1-pyrophosphate = salvageable from purine breakdown
--PPRP = not committed to making purines yet
--ten step process using 6 high energy bonds
--IMP = inosine monophosphate = first purine formed, committed to purine path
--IMP to make -->AMP (need GTP to form) and GMP (need ATP to form)
--AMP & GMP tend to be equal in amount because they promote each other's formation
--IMP + a nitrogen from aspartate --> adenosine
--xanthonsine + a nitrogen from glutamine --> guanosine
--purine rings recycled by reattaching to PPRP, emphasized in PMN's, lymphocytes, brain, liver
--defects in purine recycling --> no RNA, no proteins, brain trouble
--breakdown --> uric acid --> if not properly processed: GOUT
--KEY ENZYME of purine breakdown: xanthine oxidase, requires Mb, Fe, S, FAD
--breakdown order: remove phosphate, remove sugar, remove ammonium
Lesch Nyhan disease
--reduced affinity of key enzyme HGPRT for guanine, NO IMP SYN
--x-linked recessive, deficiency of HGPRT enzyme, several deficient forms exist
--PPRP levels increase, IMP and GMP decrease
--increase in de novo purine synthesis does not make up for lack of recycling
--S/Sx: gout, hyperuricemia, urinary tract stones, mental retardation, self-mutilation, spasticity
--allopurinol reduces gout but not mental symptoms
--PPRP cannot react with allopurinol so de novo purine synthesis does not decrease
GOUT
--we have no way to store purines, so if recycling is poor, gout, hyperuricemia
--high cell turnover rate increases gout (chemotherapy)
--deposition of sodium urate crystals in joints and kidneys (collecting ducts)
--PPRP synthetiase is abnormal in some cases--> too much purine synthesis
--HGPRT is partially deficient in other cases
--leukocytes take up crystals, rupture, release lysosomal enzymes which inflame and erode joints
--allopurinol looks like a purine
--used during chemo for pts with gout
--allopurinol limits gout by blocking formation of uric acid crystals (suicide inhibition of xanthine oxidase)
--allopurinol slows new purine synthesis by rxn with PRPP
--cochicine is anti-inflammatory used to treat gout, inhibits leukocyte movement by slowing polymerization of microtubules
PYRIMIDINES
--have a single ring
--uracil is mostly made new, used in RNA
--thymine is used in DNA, mostly recycled
--cytosine is mostly made new, used in both DNA and RNA
--ring components from glutamine, aspartate and CO2 (NO THF contribution)
--1st pyrimidine = orotic acid
--some rxns in cytosol, one in mito matrix
--pryimidine ring is made before sugar is attached
--rate lmiting enzyme is CPS II, carbamoyl phosphate synthetase II
--(CPS I goes to urea cycle, uses ammonia)
--formation of CTP from UTP requires glutamine
--CTP = cytosine triphosphate, UTP = uridine triphosphate
--uracil and thymine are recycled by two sequential rxns
--degradation --> B-alanine and B-aminoisobutyrate
SOME OTHER NUCLEOTIDE DERIVATIVES
1) ATP, GTP
2) 2nd messengers including cAMP, cGMP, cCAMP
3) coenzymes incl: NAD+, NADP+, FAD, CoA, SAM
4) UDP-glucose (glycogen metabolism)
5) UDP-glucaronic acid (phase II detox)
6) adenosine phosphosulfate (phase II detox--sulfur transfer?)