BHMT8

BHMT8

• Acutestressnorepinephrineincrease

• ThisinturnleadstoanincreaseintyrosinehydroxylasebutNOTindopaminergicnuclei

• Neteffectisincreasednorepinephrinerela:vetodopamine.

BrainRes.1991Mar22;544(1):26‐32.RelatedAr:cles,Links

EffectsofstressandadrenalectomyontyrosinehydroxylasemRNAlevelsinthelocusceruleusbyinsituhybridiza@on.

SmithMA,BradyLS,GlowaJ,GoldPW,HerkenhamM.

Sec:ononFunc:onalNeuroanatomy,NIMH,Bethesda,MD20892.

Thelocusceruleus‐norepinephrinesystemisoneoftheprincipaleffectorsofthestressresponse.Acutestressinducesnorepinephrinesynthesisandrelease,andnoradrenergiccellscompensatebyincreasingtheac:vityoftyrosinehydroxylase,therate‐limi:ngenzymeincatecholaminesynthesis.Hereweuseinsituhybridiza:onhistochemistrytoshowtheeffectsofacuteandchronicintermiYentstressontheexpressionoftyrosinehydroxylasemRNAintheratlocusceruleus.RestraintstressincreasedtyrosinehydroxylasemRNAinthelocusceruleusbutnotindopaminergicnucleisuchasthesubstan:anigraorventraltegmentalarea.OnehouroffootshockorrestraintcausedarapidincreaseinlocusceruleustyrosinehydroxylasemRNAwhichreturnedtobasallevelswithin24h.ChronicintermiYentstress(1hourofrestraintorfootshockperdayfor14days)producednochangeintyrosinehydroxylasemRNA.NeitheradrenalectomynordexamethasonereplacementsignificantlyaffectedmRNAexpression.Thesefindingsindicatethatacutestress

canincreasetheexpressionoftyrosinehydroxylasemRNAinthelocusceruleusbutthatadapta:onoccurstorepeatedstress,andthattheexpressionoftyrosinehydroxylasemRNAinthelocusceruleusisindependentofdirectglucocor:coidmodula:on.

Rememberthatsulfurcontainingaminoacidsincreasenorepinephrine,rela6onshiptoCBSupregula6ons

BHMT8appearstoincreasenorepinephrinerela@vetodopamine;alsoreflectedinbehaviors

StressandAMen@on

Leadinhibitsthisenzyme

Caspers,ML.Inhibi6onobyleadofphenylethanolamineNmethyltransferase.BiochemPharmacol.31(11):1985.1982

IncreasedCBSac:vitycanleadtoastressresponseduetosulfureffectsoncor:sollevels.

Wherethenorepinephrinereceptorisinhibitedbyhighsulfur,thisleadstoasitua:onwithhighcircula:ngnorepinephrine.

dopamine norepinephrineCopper/VitaminC

DBH

Lead

Mercury

Excessmanganese

H2S(hydrogensulfide)

Sulfides

Sulfadrugs

epinephrine

PNMT

SAMe

Methyla:onpathway

Inhibitedbylead

•CBS•SUOX•Lowmolybdenum

Norepinephrinereceptorisinhibitedby

highsulfur

STRESS

Methylgroups

cor@sol

Sulfurgroups

KidneyInt2001Jun;59(6):2267‐72Dimethylglycineaccumulatesinuremiaandpredictselevatedplasmahomocysteineconcentra@ons.McGregorDO,DellowWJ,LeverM,GeorgePM,RobsonRA,ChambersST

BACKGROUND:Hyperhomocysteinemiaisariskfactorforatherosclerosisthatiscommoninchronicrenalfailure(CRF),butitscauseisunknown.Homocysteinemetabolismislinkedtobetaine‐homocysteinemethyltransferase

(BHMT),azincmetalloenzymethatconvertsglycinebetaine(GB)toN,Ndimethylglycine(DMG).DMGisaknownfeedbackinhibitorofBHMT.WepostulatedthatDMGmightaccumulateinCRFandcontributetohyperhomocysteinemiabyinhibi:ngBHMTac:vity.METHODS:Plasmaandurineconcentra:onsofGBandDMGweremeasuredin33dialysispa:ents(15con:nuousambulatoryperitonealdialysisand18hemodialysis),33pa:entswithCRF,and33age‐matchedcontrols.Concentra:onsoffas:ngplasmatotalhomocysteine(tHcy),redcellandserumfolate,vitaminsB(6)andB(12),serumzinc,androu:nebiochemistrywerealsomeasured.Groupswerecompared,anddeterminantsofplasmatHcywereiden:fiedbycorrela:onsandstepwiselinearregression.RESULTS:PlasmaDMGincreasedasrenalfunc:ondeclinedandwastwofoldtothreefoldelevatedindialysispa:ents.PlasmaGBdidnotdifferbetweengroups.Thefrac:onalexcre:onofGB(FE(GB))wasincreasedtenfold,andFED(MG)wasdoubledinCRFpa:entscomparedwithcontrols.PlasmatHcycorrelatedposi:velywithplasmaDMG,theplasmaDMG:GBra:o,plasmacrea:nine,andFE(GB)andnega:velywithserumfolate,zinc,andplasmaGB.Inthemul:pleregressionmodel,onlyplasmacrea:nine,plasmaDMG,ortheDMG:GBra:owasindependentpredictorsoftHcy.CONCLUSIONS:DMGaccumulatesinCRFandindependentlypredictsplasmatHcyconcentra:ons.ThesefindingssuggestthatreducedBHMTac:vityisimportantinthepathogenesisofhyperhomocysteinemiainCRF.PMID:11380830,UI:21275836

AddressingStress:DMG

H2Sleadstoanincreaseinnorepinephrineandserotonin,rela@onshiptoaggression,hyperac@vityanddiversionofmethyla@oncycle

•AMen6onSupport•AmmoniaSupport•DMG•SAMe

10/06

2/07

7/07

3/07

WhyinthisinstancechoiceoftypeB12maybeimportant…roleofSAMewithrespectto

BHMT8+

2/08

9/06

10/07