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1、北大生化课件14The chemistry of glucose catabolism was elucidated over about 100 yearslThe anaerobic breakdown (fermentation) of glucose to ethanol and CO2 by yeast has been exploited for many centuries in baking and winemaking.lScientific investigation of the chemistry of glucose breakdown began in the mi
2、d-19th century.lThe complete pathway was described around 1940.Glucose is first Glucose is first phosphorylated at C-6: phosphorylated at C-6: consuming ATPconsuming ATP(Present in all cells of all organisms)Mg2+ATP2- is the actual substrateAn exergonic group An exergonic group transferring reaction
3、transferring reaction己糖激酶己糖激酶Glucose is thus trappedGlucose is thus trappedand destabilized.and destabilized.Hexokinase Hexokinase exhibits exhibits induced induced fitfit property: The binding property: The binding of of glucoseglucose in the active site in the active sitecauses a major conformatio
4、nalcauses a major conformationalchange.change.Inactive conformationInactive conformationActive conformationActive conformationGlucoseGlucoseSubstrate-induced cleftclosing is a general featureof all kinases!Glucose 6-P is then converted Glucose 6-P is then converted to fructose 6-P: via to fructose 6
5、-P: via isomerizationisomerization A reversible Isomerization reaction A reversible Isomerization reaction (intramolecular redox reaction)An aldoseA ketose磷酸己糖异构酶磷酸己糖异构酶A necessary prelude for the next two steps ofreactions (phosphorylation and C-C cleavage).Fructose 6-P is then Fructose 6-P is then
6、 phosphorylated at C-1: ATP phosphorylated at C-1: ATP consumingconsumingAnother exergonic groupAnother exergonic grouptransferring reactiontransferring reaction(PFK-1)(PFK-1)磷酸果糖激酶磷酸果糖激酶-1-1The six-carbon fructose 1,6-The six-carbon fructose 1,6-bisphosphate is then cleaved into two bisphosphate is
7、 then cleaved into two different triose phosphatesdifferent triose phosphatesThe “lysis” stepThe “lysis” step123456醛缩酶醛缩酶Interconversion between Interconversion between dihydroxyacetone phosphate and dihydroxyacetone phosphate and glyceraldehyde 3-P then occursglyceraldehyde 3-P then occurs(C3 or C4
8、)(C5 or C2)(C1 or C6)Other hexoses (e.g., Fru.,Man., Gal.) are alsoconverted to glyceraldehyde3-phosphate to enter glycolysis.A reversible Isomerization reactionA reversible Isomerization reaction (intramolecular redox reaction)磷酸丙糖异构酶磷酸丙糖异构酶An aldoseA ketoseGlyceraldehyde 3-P is then Glyceraldehyde
9、 3-P is then oxidized to form 1,3-oxidized to form 1,3-bisphosphoglyceratebisphosphoglycerateOxidation (dehydrogenation)Oxidation (dehydrogenation) followed by followed by phosphorolysis phosphorolysis An acyl phosphateAn acyl phosphate(a type of anhydride)(a type of anhydride)3-3-磷酸甘油醛脱氢酶磷酸甘油醛脱氢酶3
10、3HH3232P P3232P P3 3HHTetrameric A Cys residue is involved in the catalysis A Cys residue is involved in the catalysis of glyceraldehyde 3-P dehydrogenaseof glyceraldehyde 3-P dehydrogenaseOxidationOxidationstepstepPhosphorolysisPhosphorolysisstepstep( (An acyl-enzyme intermediateAn acyl-enzyme inte
11、rmediate) )Inactivation of the enzymeInactivation of the enzymeNADH exchanged NADH exchanged for NADfor NAD+ +3-3-磷酸甘油醛脱氢酶磷酸甘油醛脱氢酶 HB:BHBHBThe phosphoryl group linked to the The phosphoryl group linked to the carboxyl group of 1,3-carboxyl group of 1,3-bisphosphoglycerate is bisphosphoglycerate is t
12、hen transferred to ADP to form then transferred to ADP to form ATPATP(This enzyme was named for the reverse reaction)substrate-level phosphorylationsubstrate-level phosphorylation( (vs. respiration-linked phosphorylationvs. respiration-linked phosphorylation) )磷酸甘油酸激酶磷酸甘油酸激酶ADPADPATPATP3-phosphoglyc
13、erate is then 3-phosphoglycerate is then converted to 2-phosphoglycerateconverted to 2-phosphoglycerate磷酸甘油酸变位酶磷酸甘油酸变位酶Mutase: catalyzes group transferring from one position to another in a molecule.The phosphoglycerate mutase acts as a transient carrier of phosphoryl groups Phosphoglucomutase acts
14、in a similar fashion!(Initially phosphorylated by using 2,3-BPG)2-phosphoglycerate is then 2-phosphoglycerate is then dehydrated to produce dehydrated to produce phosphoenolpyruvatephosphoenolpyruvateA super high-energy A super high-energy phosphate compoundphosphate compoundDG0 for the hydrolysis o
15、f the phosphate group is changed from 17.6 to 61.9 kJ/mol.烯醇酶烯醇酶A Redistribution of energyA Redistribution of energy(PEP)The phosphoryl group of PEP is The phosphoryl group of PEP is transferred to ADP to form transferred to ADP to form ATP ATP at the endat the endThis enzyme was alsonamed for the r
16、everse reactionNonenzymaticconversion丙酮酸激酶丙酮酸激酶ADPADPATPATPThe second substrate-level ADP The second substrate-level ADP phosphorylation!phosphorylation!Major catabolic Major catabolic fates of pyruvatefates of pyruvatePyruvate also actsPyruvate also actsas precursors inas precursors inmany anabolic
17、 many anabolic reactionsreactions. .The first stage of the glycolytic The first stage of the glycolytic pathway: pathway: The preparatory phaseThe preparatory phase Glucose is activated Glucose is activated (or primed), with (or primed), with 2 ATP molecules 2 ATP molecules invested. invested.primin
18、gprimingprimingprimingisomerizationisomerizationcleavagecleavageThe second stage of the glycolytic The second stage of the glycolytic pathway: pathway: The payoff phaseThe payoff phaseOnly 5% of thepotential energy of the glucose molecule is releasedduring glycolysis.All the enzymes catalyzing glyco
19、lysishave been found in the cytosol. The net production of ATP per glucose inglycolysis is 4-2=2.The pathways of carbons, phosphoryl groups, and electronsfor glycolysis:Glycolytic enzymes may form Glycolytic enzymes may form multienzyme complexesmultienzyme complexes within cells within cellslWhen p
20、roteins are purified from extracts of broken cells in diluted solutions, noncovalent interactions between proteins could be destroyed (i.e., higher level organization destroyed).lKinetic and physical evidences suggest that the enzymes act to catalyze the ten reactions of glycolysis pathway (as enzym
21、es act in other metabolic pathways) may assemble into multienzyme complexes, where intermediates are directly channeled from one enzyme to another, without entering the aqueous solutions, a phenomenon called “substrate channeling”.The glycolyticThe glycolyticenzymes very likelyenzymes very likelyfor
22、m multienzymeform plexes.SubstrateSubstratechannelingchannelingDilutionDilutiondissociationdissociationFermentationFermentation: : pyruvatepyruvate is converted is converted to to lactic acidlactic acid or or ethanolethanol under anaerobic under anaerobic conditionsconditionsPyruvate is reducedto la
23、ctate, leading toNAD+ regenerationwhen O2 lacks (thusallowing glycolysis to continue);occurring in very active skeleton muscle, some bacteria like lactobacilliLactic acid Fermentation:乳酸脱氢酶乳酸脱氢酶Present only in those alcohol fermentativeOrganismsPresent in many organisms including humanPyruvate be de
24、carboxylatedPyruvate be decarboxylatedand reduced to form and reduced to form ethanolethanolin some microorganismsin some microorganismsEthanol Fermentation:丙酮酸脱羧酶丙酮酸脱羧酶乙醇脱氢酶乙醇脱氢酶Thiamine pyrophosphate(TPP) is involved in the cleavage of C-C bondsadjacent to a carbonylgroup. Vitamin B1 (thiamine) is
25、 used to synthesize TPP.A lack of Vitamin B1 in humans will result in a condition known as BeriberiMany carbohydrates meet their catabolic fate in glycolysislPolysaccharides such as starch and glycogen are first degraded into glucoses via hydrolysis in extracellular spaces (catalyzed by a-amylases a
26、nd other enzymes), but into glucose 1-phosphate via phosphorolysis inside cells (catalyzed by phosphorylases).lOligosaccharides (e.g., sucrose, lactose, trehalose etc) are degraded into monosaccharides before further transformed.lHexoses other than glucose can also be catabolized via the glycolytic
27、pathway after being converted to a phosphorylated derivative.HOHOHOHa a-amylasePentose phosphate Pentose phosphate pathwaypathway converts converts glucose to specialized glucose to specialized products needed by products needed by cell biosynthesis: cell biosynthesis: NADPHNADPH and and Ribose 5-Ri
28、bose 5-phosphatephosphateThis is primarily an anabolic pathway.To counter the damagingeffects of oxygen radicalsFor Reductive biosynthesisSome biological roles served by PPPNucleotidebiosynthesisPPP in rapidlydividing cellsGlucoseGlycogenCyclic esterThe Non-oxidative phase of PPPIsomerization &epime
29、rization of Ru5PCarbon-carbon bond cleavage and formationTPPTPP转羟乙醛酶转羟乙醛酶转二羟丙酮基酶转二羟丙酮基酶Ribulose 1,5-bisphophate is regenerated alsovia this pathway in the Calvin cycle.GlycolysisTwo other ways ofdisplaying the PPPTPP is involved in the C-C cleavage and formation reaction catalyzed by transketolase:
30、transferringtwo carbons from a ketose to an aldose. Transaldolase catalyzes a reaction in which a three-carbonunit is transferred from a ketose to an aldose without being helped by any cofactor.G-6-P is partitioned between glycolysis and PPPSummary (1)lD-glucose is a commonly used fuel and D-glucose
31、 is a commonly used fuel and versatile precursor in almost all versatile precursor in almost all organisms.organisms.lThe study of glucose degradation has a The study of glucose degradation has a rich history in biochemistry (especially rich history in biochemistry (especially for enzymology).for en
32、zymology).lGlucose is first converted into two three-Glucose is first converted into two three-carbon pyruvates via the ten-step carbon pyruvates via the ten-step glycolysis pathway without directly glycolysis pathway without directly consuming Oconsuming O2 2 and with a net production of and with a
33、 net production of two ATP molecules by substrate-level two ATP molecules by substrate-level phosphorylation.phosphorylation.lLimited amount of energy can be released Limited amount of energy can be released by oxidizing glucose under anaerobic by oxidizing glucose under anaerobic conditions by ferm
34、entation.conditions by fermentation.lThe enzymes participating glycolysis may The enzymes participating glycolysis may form multiple enzyme complexes, where form multiple enzyme complexes, where substrate is channeled from one enzyme to substrate is channeled from one enzyme to another.another.lThe
35、sugar units on glycogen is converted The sugar units on glycogen is converted to glucose 1-phosphate via phosphorolysis, to glucose 1-phosphate via phosphorolysis, which is catalyzed by glycogen which is catalyzed by glycogen phosphorylase.phosphorylase.lGlucose 6-phosphate can also be oxidized Glucose 6-phosphate can also be oxidized to form ribose 5-phosphate and NADPH via to form ribose 5-phosphate and NADPH via the pentose phosphate pathway.the pentose phosphate pathway.Summary (2)
