L11 oxid stress Flashcards
Types of ROS dam
-ROS dam DNA-
Reac with base- modif can= misp and mut (fail rep).
Reac with sug- can=str break and mut on rep.
ROS dam DNA= fail rep can lead to mut and poss CA. Amnt 8 oxo dG in cells can meas prev oxid dam. DeoxyG conv to 8oxodG by ROS.
MtDNA esp sensit as near IM where ROS formed. And nor protec by histones.
-ROS dam prot- (see diag)
Dam backb=frag and prot deg. Dam s/c= modif AA eg carbonyls, hydroxylat, ring open, dimers, inapp S-S= alt prot struc can GoF or LoF.
S-S imp in fold and stabil esp sec prots or in EC domains of mem prots. Btw thiol grps of cys. Inapp if ROS take e- from cys=misf, X link and disrup func eg enz. Eg Heinz bod precip X linked Hb.
-ROS dam lip- (see diag).
Unsat lip+OH- makes lip radic. Propag by O2 makes lip peroxyl radic. To lip peroxide.
FR extract H from polyunsaturated FA in mem lip. Lip radic can reac with O2=lip peroxyl radic= propag, this radicalises nearby chains. Chain reac as peroxyl extrac H from near FA. Phob env of bilat disrup and mem integ fails.
-link lip transp- incr serum LDL apoC atheroscler.
Sources biol oxidants
-endog (cell)- ETC, NO synthases, NADPH oxidases. Less imp- peroxidases, lipooxygenases, xanthine oxidases, monamine oxidases.
-exog- radiat- cosmic rays, UV, X Ray. Pollutants. Drugs eg primaquine antimalarial. Tox eg Paraquat herbicide.
-ETC- occas e- esc chain and reac with diss O2 to form superox. Quite freq but mito enz immed deal with.
-NOS- diag
INOS- inducib NOS prods lot NO in phagoc= dir tox eff.
ENOS- endoth (sig).
NNOS- neuronal (sig). Last 2 lower concs.
LO3: outl cell defs against ROS.
-superox dismutase and catalase- diags
SOD conv superox to H2O2 and O2. Prim def because superox is string init of chain reacs. 3 isoenzs: Cu Zn cytos and EC. MN mito.
Catalase conv H2O2 to water and O2. Widespread. Imp in imm cells protec against oxid burst.
-glutathione- diags
Tripep synth in bod NOT encod. Cys thiol donate e- to ROS. GSH reac with other= GSSG disulph glutathione perox reqs selenium.
GSH gamma pep link btw COOH of glu and NH2 of cys. V abund in cells. GSSG recyc/reduced back to GSH by GSH reductase, canals tranf e- from NADPH to S-S. NADPH from PPP Essen in protec from FR dam.
-FR scav- diag
Vit E lip sol antioxidant. Imp protec against lip peroxidat. Donate e- instead of FA dam, scav FR prev dam.
Vit C ascorbic ac water sol. Imp in regen reduced vitE.
Others- carotenoids, Uric ac, flavonoids, melatonin.
FR scav reduce FR dam by donat H to FR in non enz reac.
Oxid stress
-when def compromise or excess burden oxidant. Def us keep homeo.
Oxidants eg superox, h perox, hydroxyl, NO-, ONOO-.
Defs eg SOD, GSH, catalase, NADPH, vit E and C.
Is int in inflamm reac eg iNOS enz prod lot NO- is conv to ONOO-.
Resp burst (diag)
-rap rel superox and H2O2 from phagoc cells eg neut, monoc. ROS and ONOO- destr invading bact and phagolysos.
Chronic granulomatous dis- genet defec NADPH oxidase= incr suscep to bact infec as no resp burst. atyp infec eg pneum, abcess, impetigo, cellulitis.
Cell us destr self as well as microbe.
NADPH oxidase trans e- from NADPH cross mem to couple to O2= superox. Myeloperox to hypochlorite.
LO4: expl role oxid stress in dis states.
-galactosaemia- diag
Incr aldose reductase consumes NADPH. Compromise def Ag ROS. Crystallin prot in eye lens denat= cataract. Also galactitol incr osmot press=lens swell and rupt.
Defic of galactokinase, uridyl/t (most comm), or UDP galac epimerase. Means galaxy conv to galactitol using NADPH. NADPH imp in recyc GSH To protective reduced form. Also compon of SOD complex etc.
Symps- hepatomeg and cirrhosis. Renal fail. Vom. Seiz and brain dam. Cataracts. Hypog.
-G6PDH defic- diag
Imp in PPP, Maj source NADPH. Catals gluc 6P to 6P gluconate= format of NADPH. 6P gluconate then ent glycolysis or nt bios via PPP which also prods NADPH. In RBC, PPP only source of NADPH and risk from oxidative env as O transp.
Oxid stress eg infec, drugs, broad beans forms H2O2. Lip peroxidat- cell mem dam eg RBC, lack deform=mech stress, can’t through capills. Prot dam- aggregs of X linked Hb=Heinz bods- dark stain on. RBC from precip Hb. Bind mem and make RBC rigid. Spleen rem helix bods= blister cells.
-metab of paracetamol- in hepatoc- diag
NAPQI tox metabol strng ax indisting agent, uses up GSH. NAPQI direc tox eff by cov bond hepat prots, can =liv fail if not treat. Indirect dam by GSH deplet. Acetyl cys Tx replenish GSH, need give in 8hr of OD.
-isch repurf inj-
Heart, brain, organ transplant. Cells Rev inj due to ST isch can recov if restor blood flow.
BUT repurf oxy blood can= more dam (esp mito) than init isch. Incompl metabolised prods accum as low O= prod ROS on re intro of O. Loss antioxidants dur isch. Influx Ca on renew blood flow. Rec leucocytes to aff area.
LO1: desc prod of superox radio by mito.
LO2: disc other ROS and RNS sp.
-cell dam by ROS and RNS is compon in lot of dis eg CVD, alz, RA, crohns, COPD, isch/repurf inj, CA, pancreatitis, Parkinson’s, MS. Antioxidant defs overwhelmed.
-free rads- e- of atom/molec/ions us assoc in pairs. Each pair moves on orbital. FR= atom or molec 1+ unpaire e- capab of indep/free exist. Eg OH-. Us v reac, acq e- form other atoms/molec/ions. O2 not. Reac FR and molec typ gens 2nd FR= propag dam.
-ROS- in ETC 0.1-2% e- not reach end chain and premat reduce O= superox. Then propag. (See diag).
FR also prod by ionic rad, contrib to cell dam. Are also inv in ageing. Some tox eg Paraquat herbicide= prod superox.
