化学生物学氨基酸性质一构型

Lecture3.Aminoacids,peptidesandPengChen,DepartmentofChemicalBiologyCollegeofChemistry,PKUProteinsaremolecularmachinesinProteinsareorganic生物体内(NaturalOccurringAminoAcid)R O

氨基酸的性质(一):构 手性中心(Chiral H3NO

(Main-

O蛋氨酸Methionine

丙氨酸Alanine

甘氨酸GlycineH2H2NC谷酰胺GlutamineQ)精氨酸Arginine(R)丝氨酸Serine(S)苏氨酸Threonine

半胱氨酸Cysteine天冬氨酸Asparticacid(D)谷氨酸Glutamicacid(E)组氨酸Histidine(H)异亮氨酸Isoleucine亮氨酸Leucine

O氨基酸的性质(二):等电点(IsoelectricpH滴pH滴定曲lowhigh

(B:-HA+HA+酸B:-+碱[HA]=[B:-

甘氨酸盐酸盐的甘氨酸盐酸盐的滴定《基础有机化学(邢其毅等)》第1010(IsoelectricPoint,IP)氨基酸的性质(三):生物体内的(Acid/Baseequilibriain生命之pH值大都通过缓冲溶液控制在7-7.5这类氨基酸的等电点一般在pH值=6.2-6.8中性氨基酸的体内酸碱

00生理pH

0氨基酸的性质(四):侧链的酸碱性OOOAspOGlu+N+H22N+OHisOLysOArgpH=2.8- 生理酸碱性生理酸碱性(Physiological

生理酸、碱的

生理pH(Physiological[H3O+]=[HO- 质子化状态(Protonation

++N+N

+

O O

OO

+

Arg 阴离子为主与溶中性形式阳离子为活氨基酸的性质(五):侧链的极性HSROAlaOValOIleOLeuOMetOOHS+OSerOOThrOAsnOGln+NHHN++++OHisOOTyrOTrp++O(Metalligands)C

O.N+NHO.N+NH 高稳定性t1/2@pH7:~10年O

K=10-

H H

G‡=20除脯氨酸外，cis-肽键非常少

多肽(二)：结构与N （Glu-Gly-Ala-Insulinhexamer(51 Ubiquitin(76Oneconventionisthatthosepeptidechainsthatareshortenoughtobemadesyntheticallyarecalledpeptidesratherthanproteins.However,withtheadventofbettersynthetictechniques,peptidesaslongashundredsofaminoacidscanbemade,includingfullproteinslikeubiquitin.Anotherconventionplacesaninformaldividinglineatapproxima y50aminoacidsinlength(somepeopleclaimshorterlengths).However,thisdefinitionissomewhatarbitrary.Longpeptides,suchastheamyloidpeptidelinkedtoAlzheimer’sdisease,canbeconsideredproteins;andsmallproteins,suchasinsulin,canbeconsideredpeptides.Peptide

RibosomalNonribosomalSynthetic

PeptideStructuralbiologyPeptideRibosomalpeptidesSynthesizedbytranslationofmRNA.TheyareoftensubjectedFunction,typicallyinhigherorganisms,ashormonesandsignalingmolecules.Someorganismsproducepeptidesasantibiotics,suchasThyrotropin-releasinghormoneGlucagon,a29aa.RibosomalpeptidesTheaminoacidresiduesinvolvedarerestrictedtothoseutilizedbytheribosome.However,thesepeptidesfrequentlyhaveposttranslationalmodifications,suchasphosphorylation,Ingeneral,theyarelinear,althoughlariatstructureshavebeenobserved.Moreexoticmanipulationsdooccur,suchasracemizationofL-aminoacidstoD-aminoacidsinplatypusvenom.Non-ribosomalpeptidesAssembledbyenzymesthatarespecifictoeachpeptide,ratherthanbytheribosome.Themostcommonnon-ribosomalpeptideisglutathione,whichisacomponentoftheantioxidantdefensesofmostaerobicorganisms.Othernon-ribosomalpeptidesaremostcommoninunicelluarorganisms,plants,andfungiandaresynthesizedbymodularenzymecomplexescallednon-ribosomalpeptidesynthetases.Non-ribosomalpeptidesThesepeptidesareoftencyclicandcanhave plexcyclicstructures,althoughlinearnonribosomalpeptidesarealsocommon.Sincethesystemiscloselyrelatedtothemachineryforbuildingfattyacidsandpolyketides,hybridcompoundsareoftenfound.Oxazoles,thiazolesoftenindicatethatthecompoundwassynthesizedinthisfashion.StructuralbiologyPeptideshaverecentlybeenusedinthestudyofproteinstructureandfunction.Forexample,syntheticpeptidescanbeusedasprobestoseewhereprotein-peptideinteractionsoccur.ProteindenovoFourhelixWillamDeGrado,Univ.通常把分子量大于1万(1KDa蛋白质主链的RHONHN 角与:CO-N-C-:N-C-CO-=

=

=-

=

=-

=

N

N

N

蛋白质的二级氢氢反平氢平残基/转残基/圈上升/残基1.5上升/圈5.4C/C距离3.6氢键残基 残基

俯视13元反平行-平行-MiniatureAlannaSchepartz,PeptideinhibitorsorInhibitorypeptidesarealsousedinclinicalresearchtoexaminetheeffectsofpeptidesontheinhibitionofcancerproteinsandotherdiseases.Advantagesand

HIVStapledBarbaraImperiali,CellpenetratingCPPsareofvariousdifferenttypesandsizes,butinmostcases,thefunctionallysignificantpartofthepeptidesseemstobeasequenceofaminoacidsabout10residuesinlengthandrichinaminoacidswithpositivelychargedsidegroups(e.g.Arg,Lys).PeptideSolutionphase

Cheap,ShortBasicprinciplessolid-phaseRobertBruceMerrifield

AutomaticpeptideResin CH2 CH2 HC Merrifield

Resin BHR ROONROO NH

Cl-tritylOOOProtectingBoc-O N H

NR

R +H

H3N+OH OONOH OONNO

+H3N

CouplingNC

RAmino

Activatedamino

O

NCNCNCNCNExample:SynthesisofAla-Gly-Leu-

O

OOHDCC/CH2Cl O

N

O

O H OO

O

OH2C OHDCC/CH2Cl

O

O N

O N

F全球胰岛素销售额>100中国胰岛素市场份额>100亿自古代就已被发现，最早记载于西元一千五百年前的古埃及[2][3][3]。 直到19