ETOX 202

Macromolecular Target Clofibrate
Macromolecular Target Clofibrate = PPAR
Macromolecular Target Lead
Macromolecular Target Lead = ALAD
Macromolecular Target Pertussis Toxin
Macromolecular Target Pertussis Toxin = G-protein Gα-i
Macromolecular Target Cholera Toxin
Macromolecular Target Cholera Toxin = G-protein Gα-s
Macromolecular Target Dioxin/TCDD Order Sensitivity
Macromolecular Target  Dioxin = Ah Receptor must bind with AHR/HSP90/ARA9 HIF is competitor weightloss is correlation not caused by p450 induction Amino acid Ile 332/ser makes more sensitive, ILE/ala, Val/ala
Macromolecular Target  Botulinum A Toxin
Macromolecular Target  Botulinum A = VAMPS
Macromolecular Target Parathion
Macromolecular Target  Paration = AchE
Macromolecular Target  Muscarine
Macromolecular Target  Muscarine = Mucarinic Receptor
Macromolecular Target  Nicotine
Macromolecular Target  Nicotine = Nicotinic Receptor
Macromolecular Target  Tubocurare
Macromolecular Target Tubocurare = Nicotinic neuromuscular acetylcholine receptors
G-Protein linked Receptor Sequence
Ligand binds to GPCR causing activation and conformational change GDP bound to Gαs is replaced by GTP and G-beta and G-gamma dissociates from G-alpha G-alpha binds to adenylyl cyclase to activate it causing it to catalyze formation of cAMP, raising cAMP levels cAMP dependant protein kinase causing activation of pka pka goes into the nucleous, Atp ->ADP activates CREB by phosphorylation CBP binds to CREB and then binds to cAMP response element causing transcription G-beta activates phospholipase C which cleaves IP3 from biphosphate and activates Ca2+ channels in ER Ca2+ activates protein kinase C
Diptheria Toxin Sequence
Two Domains:A = Catalytic DomainB = Transmembrane/Receptor Domain Low iron, uses siderophores to sequester and produces toxin. High iron no toxin made A & B Toxins are cleaved by protease but stay together due to a disulfide bond. The cleaveing activates dip. tox.   binds to HB-EGF and enters cell through endocytosis The proton pump by V-type ATPase causes acidification 7 to 6 in vacuole resulting insertion into the membrane A domain is fully cleaved from B domain, A domain crosses the membrane and affects EF2 function by inhibiting the translocation of tRNA from A-site to P-site
Critical Amino Acids in epoxide Hydrolase and why
Y381-OH and Y465-OH hydrogen bond with the O on epoxide faciltates nucleophilic attack by ASP333-COO- attcks epoxide ring leading to formation of hydroxylacyl intermediate His523 and ASP495  hydrolyze the intermediate allowing ASP333-COOH to disassociate
Cholinergic neuromuscular junction sequence
Ca2+ enters and binds to SNARE complex (VAMP & SNAP on vesicles) ,opening Ca2+ ion channels Once bound, the vesicle is docked on presynaptic membrane and releases neurotransmitters.

Ach binds to AchR on post synaptic vessicle and triggers transmission of signal flow. Na+ enters cells and depolarizes, if threshold is reached and action potential triggers. Sarcolema repolarizes as K+ flows, NA/K pump restores ions.

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 AcHE cataylzes degradation of Ach in synapse.

CYP1A1 regulation
Dioxin binds to AhR, AhR and Arnt attach to Dioxin repsonse element CYP1A1 expressed
CYP3 Expression CYP3A4
Steriod (Rifampicin) binds to PXR, cis-9-retinoic acid binds to RXR PXR and RXR attach to XREM
CYP4 Expression
colfibrate binds to PPAR, Cis-9-retinoic acid binds to RXR PPAR and RXR attach to PPRE CYP4 expressed
CYP7 Expression
fatty acids/cholesterol binds to LXR, CXR LXR and CXR attach to LXRECYP1A1 expressed
CYP2B Expression
Phenobarbital binds to CAR, cis-9-retinoic acid binds to RXR, CAR and RXR attach to Phenobarbital repsonse element 
Important Amino Acids in Glutathione
Normally GSH is pH7 then when bound to GST pH 5-6, GSH is not very active but is in presence of GST. Alpha is most predominate Gsite and binds to GSH, H site is lipophilic and binds to substrate Y-6 on G site forms the electrophile pocket, its acidic and allowing gsh to be ionized and perform nucleophilic attack on epoxide, S-209 forms hydrophobic pocket, facilliating Y115 Y-115 acidic h site, forms the substrate pocket, is electron acceptor
BAP Carcinogens
(+)7,8 diol 9,10 epoxide-2 (anti)(-)7,8 diol 9,10 epoxide-1 (syn)(+)7,8 diol 9,10 epoxide-1 (syn)(-)7,8 diol 9,10 epoxide-2 (anti)  
Reporter bashing
Take regulatory part of gene and attach a reporter gene. Remove parts of regulatory gene and monitor reporter to know which part of gene is important
mEH and sEH
mEH – Cis, microsomal epoxide hydrolase, ER metabolismsEH- Trans, soluble epoxide hydrolase, cytoplasm metabolism
Arachidonic acid
Cox pathway -> painLOX pathway -> Leukotriene = allergiesCYP2 Epoxygenase -> EETs = hypertension adds epoxide to any double bondCYP4 hydrolase -> Hetes Adds adds an OH to CH3
Leukotrine Steps
Leukotrine A4 -> LTB4 by hydrolase no acyl groupor A4-> C4 Glutathioe transferase loses glutamic acidc4-> d4 CGP takes off glycine and becomes acetyl groupd4->e4 acetyl group is transfered becomes aminee4 -> f4 formation mercapturic acid
UDGP Pathway
Toxin enters membrane, gets metabolized by P450, goes to UDPGA, UGT->UDP, and then leave cell as toxin-glucuronide,UDP -> UDPse -> UMP -> Translocase trades cytoplasm UDPGA into ER from UMP to cytoplasm
Target for pyrethroids
Na Channel
Target for diazapines
sodium/potasium pump
P-type pumps, f-type pumps, v-type pumps, abc transporter
p = ion pump ATP to pump outf-type = H+ pump builds ATP and makes acidicV-type = same as f type but in vacuoleABC uses 2 ATP to pump molecule out
Dimerization of AHR/ARNT
bHLH is DNAbinding with PAS-A, secondary dimerizization is PAS, B is ligand binding,
Clostridium c2 toxin target
actin
Picolo Toxin target
GABA a
Tetanus Toxin and botulism toxin mechanism
binds Bot A. binds to SV2, bot. B binds to synaptotagmin, inside vesicle before it budsbuds and retrograde transport into the cell,acidification inside vesicle due to atpase proton pumpconformation change allowing inserting into membraneA domain is release in cytoplasmBot A. cleaves SNAP-25Bot B.

cleaves synaptobrevinTetanus cleaves VAMPleads to no vesicle docking and no neurotransmitter release

ParasympatheicSympathetic
Parasympathetic: Long pre, short Post, AchSympathetic: short pre long post,Ach, Ne
Muscarinic receptorNicotinic receptor
Muscarinic = gprotein receptorNicotinic = ligand gated
Atropine target
Muscarinic receptor
Types of receptorsGABA A & CGABA-B
Transmitter gated channel = GABA A&CGPCR – GPCR
Important Amino Acids of ACHE
Peripheral site – allow the substrate to enter, determine affintiy, W279,Y121,F330Catalytic site – charged residue of Ache, this is required for binding, S200, Hist440, E327
AchE ageing
organophoste binds to ACHE, ethylene is removed, permanant addition
GSH reacts with dibromide
GS is – and H is +GS attacks Br//Br -> SG//Br- -> GS+ triangle
SULT
HIST 108 extract proton from OH and Sulfate, another OH attacks sulfur in SULT producing and intermediate-OH on substrate becomes -OSO3
Nicotine pathway
Nicotine -UGT-> add Glu onto empty NNicotine -CYP2-> add =O on CH2 to the right of N-CH3 -UGT-> to add glu onto emtpy NNicotine -CYP2-> add =O on CH2 to the right of N-CH3 -CYP2-> -OH to right of =O -UGT-> -OH to -OGlu
BAP Pathway
BAP is 2 on top of 3 ringsP450 add epoxide on bottom left or top left and its either down or up. Epoxide hydrolase makes them OH’s the one closest to the bay region matches up/down of epoxide other -OH is opposite. then P450 act on which ever it didn’t act on fisrt making another epoxide. Epoxide hydrolase can break and then It can then react with N7 on DNA and then be removed by aicd hydrolysis.If GST/GSH breaks 2nd you get -oh -SG