Central Metabolism

The Topic deals with the important biochemical cycles related to carbohydrate metabolism

1. Biochemistry-
Central metabolism
SONY PETER
MINISTRY OF EDUCATION
MIZAN-TEPI UNIVERSITY
ETHIOPIA

2. Definition
CarbohydrateMetabolism
a.Glycolysis&TCACycle
b.Gluconeogenesis
c.Glycogenesis&Glycogenolysis
d.GlucoseHomeostasis
Normalvalues
Supplyofglucosetoblood
Removalofglucosefromblood
e.Clinicalcorrelates
Glycogenstoragedisorders
Fastingstoragedisorders
Fastinghyperglycemia
Fastinghypoglycemia

3. Definition-Carbohydratemetabolismdenotesthe
variousbiochemicalprocessesresponsiblefor
theformation,breakdown,andinterconversion
ofcarbohydratesinlivingorganisms.Digestionbreaks
down complexcarbohydratesintoa few
simplemonomersformetabolism:glucose,fructose,
andgalactose.
-Glucoseconstitutesabout80%oftheproducts,andisthe
primarystructurethatisdistributedtocellsinthetissues,
whereitisbrokendownorstoredasglycogen.

4. -In aerobic respiration, the main form of cellular respiration
used by humans, glucose andoxygenare metabolized to
release energy, withcarbon dioxideandwateras
byproducts.Most of the fructose and galactose travel to the
liver, where they can be converted to glucose.

6. Glycolysis & TCA Cycle
What is Glycolysis?
Glycolysisisthemetabolicpathwaythat
convertsglucoseC
6H
12O
6,intopyruvate,CH
3COCOO
−
+H
+
.
Thefreeenergyreleasedinthisprocessisusedtoformthe
high-energymoleculesATP(adenosinetriphosphate)and
NADH(reducednicotinamideadeninedinucleotide).

8. Glycolysisproduces2ATP,2NADH,and2pyruvate
molecules:Glycolysis,ortheaerobiccatabolicbreakdownof
glucose,producesenergyintheformofATP,NADH,and
pyruvate,whichitselfentersthecitricacidcycletoproduce
moreenergy.
FourtotalmoleculesofATPareformed
duringglycolysis.Two,however,areusedduring
theglycolysisreactions.Sothenetgainis2.

9. Thesequenceofglycolysisreactionisseparatedintotwo
phases
1.Thepreparatoryphase
2.Thepay-offphase

10. PreparatoryPhase
Preparatoryphaseisthestageinwhichthereisconsumption
ofATPandisalsoknownastheinvestmentphase.Thepay-
offphaseiswhereATPisproduced.Thefirstfivestepsofthe
glycolysisreactionisknownasthepreparatoryor
investmentphase.Thisstageconsumesenergytoconvertthe
glucosemoleculeintotwomoleculesthreecarbonsugar
molecule.

11. Step1
Thesteponeinglycolysisisphosphorylation.Thisstep
glucoseisphosphorylatedbytheenzymehexokinases.Inthis
process,ATPmoleculeisconsumed.Aphosphategroupfrom
theATPistransferredtotheglucosemoleculestoproduce
glucose-6-phosphate.
Glucose + Hexokinase + ATP → Glucose-6-phosphate + ADP
(C
6H
12O
6) (C
6H
11O
6P
1)

12. Step1

13. Step2
Thesecondstageofglycolysisisanisomerizationreaction.
Inthisreactiontheglucose-6-phosphateisrearrangedinto
fructose-6-phosphatebytheenzymeglucosephosphate
isomerase.Thisisareversiblereactionundernormal
conditionsofthecell.
Glucose-6-phosphate+Phosphoglucoisomerase→Fructose-6-phosphate
(C
6H
11O
6P
1) (C
6H
11O
6P
1)

14. Step2

15. Step3
Inthethirdstepofglycolysisisaphosphorylationreaction.
Inthissteptheenzymephosphofructokinaseistransfers
phosphategrouptoformfructose1,6-bisphosphate.Another
ATPmoleculeisusedinthisstep.
Fructose6-phosphate+phosphofructokinase+ATP
(C
6H
11O
6P
1)
→Fructose1,6-bisphosphate+ADP
(C
6H
10O
6P
2)

16. Step3

17. Step4
Thisstepinglycolysisisadestabilizationstep,whereathe
actionoftheenzymealdolasesplitsfructose1,6-
bisphosphateintotwosugars.Thesesugarsareisomersof
eachother,theyaredihydroxyacetonephosphateand
glyceraldehydephosphate.
Fructose1,6-bisphosphate+aldolase
(C
6H
10O
6P
2)
→Dihydroxyacetonephosphate+Glyceraldehydephosphate
(C
3H
5O
3P
1) (C
3H
5O
3P
1)

18. Step4

19. Step 5
Step5ofglycolysisisaninterconversionreaction.Here,the
enzymetriosephosphateisomeraseinterconvertsthe
moleculesdihydroxyacetonephosphateandglyceraldehyde
phosphate.
Dihydroxyacetone phosphate→ Glyceraldehyde phosphate
(C
3H
5O
3P
1) (C
3H
5O
3P
1)

20. Step5
Thisstepmarkstheendofthepreparatoryortheinvestment
phaseofglycolysis.Soattheendhere,the6-carbonglucose
moleculeissplitintotwothree-carbonmoleculeswiththe
expenseoftwpATPmolecules.

22. Pay-off Phase
Thesecondphaseofglycolysisisknownasthepay-off
phaseofglycolysis.Thisphaseischaracterizedbygainof
theenergy-richmoleculesATPandNADH.

23. Step6
Thisstepofglycolysisisadehydrogenationstep.The
enzymetriosephosphatedehydrogenase,dehydrogenates
glyceraldehyde3-phosphateandaddsaninorganic
phosphatetoform1,3-bisphosphoglycerate.Firstly,the
enzymeactiontransfersaH-(hydrogen)from
glyceraldehydephosphatetotheNAD+whichisan
oxidizingagenttoformNADH.Theenzymealsoaddsa
inorganicphosphatefromthecytosoltotheglyceraldehyde
phosphatetoform1,3-bisphosphoglycerate.Thisreaction
occurswithboththemoleculesproducedinthepreviousstep.

24. 2Glyceraldehydephosphate+Triose
(C
3H
5O
3P
1)
phosphatedehydrogenase+2H-+2P+2NAD+
→two1,3-Bisphosphoglycerate+2NADH+2H+
(C
3H
4O
4P
2)

25. Step6

26. Step7
Step7ofglycolysisisasubstrate-levelphosphorylation
step,wheretheenzymephosphoglycerokinasetransfersa
phosphategroupfrom1,3-bisphosphoglycerate.The
phosphateistransferredtoADPtoformATP.Thisprocess
yieldstwomoleculesof3-phosphoglyceratemoleculesand
twomoleculesofATP.TherearetwomoleculesofATP
synthesizedinthisstepofglycolysis.
2 molecules of 1,3 bisphophoglycerate (C
3H
4O
4P
2)+
phosphoglycerokinase + 2 ADP →2 molecules of 3-
phosphoglycerate (C
3H
5O
4P
1) + 2 ATP

27. Step7

28. Step8
Thisstepofglycolysisisamutasestep,occursinthe
presenceoftheenzymephosphoglyceratemutase.This
enzymerelocatesthephosphatefromthe3-
phosphoglyceratemolecularthirdcarbonpositiontothe
secondcarbonposition,thisresultsintheformationof2-
phosphoglycerates.
2moleculesof3-phsophoglycerate(C
3H
5O
4P
1)+
phsosphoglyceromutase→2moleculesof2
Phosphoglycerate(C
3H
5O
4P
1)

29. Step8

30. Step9
Thisstepofglycolysisisalyasereaction,whichoccursin
thepresenceofenolaseenzyme.Inthisreactionthe
enzymeremovesamoleculeofwaterfrom2-
phosphoglyceratetoformphosphoenolpyruvicacid(PEP).
2 molecules of 2-phosphoglycerate (C
3H
5O
4P
1) + enolase
→ 2 molecules of phosphoenolpyruvic acid (PEP)
(C
3H
3O
3P
1) + H
2O

31. Step9

32. Step 10
Thisisthefinalstageofglycolysiswhichisasubstrate-
levelphsophorylationstep.Inthepresenceoftheenzyme
pyruvatekinase,thereistransferofainorganicphosphate
moleculefromphosphoenolpyruvatemoleculetoADPto
formpyruvicacidandATP.Thisreactionyields2molecules
ofpyruvicacidandtwomoleculesofATP.
2moleculesofPEP(C
3H
3O
3P
1)+pyruvatekinase+2ADP→
2moleculesofpyruvicacid(C
3H
4O
3)+2ATP
Thisreactionmarkstheendofglycolysis,herebyproducing
twoATPmoleculesperglucosemolecule.

33. Step 10

36. Glycolysis Pathway

37. TCA Cycle

39. Thecitricacidcycle(CAC)–alsoknownasthetricarboxylic
acid(TCA)cycleortheKrebscycleisaseriesofchemical
reactionsusedbyallaerobicorganismstoreleasestored
energythroughtheoxidationofacetyl-CoAderived
fromcarbohydrates,fats,andproteinsintocarbon
dioxideandchemicalenergyintheformofadenosine
triphosphate(ATP).

40. TCA
Cycle
ATP
CO
2

41. The tricarboxylic acid cycle (TCA cycle, also called the Krebs
cycle or the citric acid cycle) plays several roles in metabolism.
It is the final pathway where the oxidative metabolism of
carbohydrates, amino acids, and fatty acids converge, their
carbon skeletons being converted to CO2. This oxidation
provides energy for the production of the majority of ATP in
most animals. The cycle occurs totally in the mitochondria and
is, therefore, in close proximity to the reactions of electron
transport, which oxidize the reduced coenzymes produced by
the cycle. The TCA cycle is an aerobic pathway, because O2 is
required as the final electron acceptor. Most of the body's
catabolic pathways converge on the TCA cycle.

42. The citric acid cycle also supplies intermediates for a number
of important synthetic reactions. For example, the cycle
functions in the formation of glucose from the carbon skeletons
of some amino acids, and it provides building blocks for the
synthesis of some amino acids and heme.
Aerobic metabolism of carbohydrate is carried out in two
phases.
a)Pyruvate produced by glycolysis is first oxidatively
decarboxylated to Acetyl-coA by pyruvate dehydrogenase.
b)Acetyl-coA is then oxidized in the TCA cycle.

44. Theacetyl-CoA,hasbeenoxidizedtotwomoleculesof
carbondioxide.
ThreemoleculesofNADwerereducedtoNADH.
OnemoleculeofFADwasreducedtoFADH2.
OnemoleculeofGTP(theequivalentofATP)was
produced.
Keepinmindthatareductionisreallyagainofelectrons.
Inotherwords,NADHandFADH
2moleculesactas
electroncarriersandareusedtogenerateATPinthenext
stageofglucosemetabolism,oxidativephosphorylation.

45. It is the formation of glucose from non-carbohydrate materials
in liver and renal cortex. Lactate and pyruvate are quantitatively
the largest source of glucose in gluconeogenesis, particularly in
intense exercise. Next comes the glucogenic amino acids such as
glycine and alanine, during starvation, gluconeogenesis takes
place mainly from amino acids.

47. Regulation of gluconeogenesis
Theregulationofgluconeogenesisandglycolysisinvolves
theenzymesuniquetoeachpathway,andnotthe
commonones.
Whilethemajorcontrolpointsofglycolysisarethe
reactionscatalyzedbyPFK-1andpyruvatekinase,the
majorcontrolpointsofgluconeogenesisarethereactions
catalyzed by fructose 1,6-
bisphosphataseandPyruvatecarboxylase.

48. •Theothertwoenzymesuniquetogluconeogenesis,
glucose-6-phosphataseandPEPcarboxykinase,are
regulatedattranscriptionallevel.

49. Glycogen Metabolism
GLYCOGENESIS
Glycogenesis is the synthesis of glycogen from glucose in the cytosol. Mainly the liver and
muscles and to lesser extent, many other tissues, except mature erythrocytes, brain and
kidneys, carry out glycogenesis.Glucose (1) glucose 6 -phosphate (2) glucose 1-phosphate (3)
UDP-glucose (4) glycogen amylose (5) glycogen

(1)Hexokinase or glucokinase
(2)Phospho glucomutase
(3)UDP-glucose pyrophosphorylase
(4)Glycogen synthase
(5)Branching enzyme

50. Theenzymeglycogeninisneededtocreateinitialshort
glycogenchains,whicharethenlengthenedandbranched
bytheotherenzymesofglycogenesis.Glycogenin,a
homodimer,hasatyrosineresidueoneachsubunitthat
servesastheanchorforthereducingendofglycogen.
Initially,abouteightUDP-glucosemoleculesareaddedto
eachtyrosineresiduebyglycogenin,formingα(1→4)
bonds.

51. •Onceachainofeightglucosemonomersis
formed,glycogensynthasebindstothegrowingglycogen
chainandaddsUDP-glucosetothe4-hydroxylgroupof
theglucosylresidueonthenon-reducingendofthe
glycogenchain,formingmoreα(1→4)bondsinthe
process.
•Branchesaremadebyglycogenbranchingenzyme(also
knownasamylo-α(1:4)→α(1:6)transglycosylase),which
transferstheendofthechainontoanearlierpartviaα-1:6
glycosidicbond,formingbranches,whichfurthergrowby
additionofmoreα-1:4glycosidicunits.

54. Glycogenolysis
•Glycogenolysis is a catabolic process; the breakdown of glycogen to
glucose units.
•Glycogen is principally stored in the cytosol granules of -
•Liver
•Muscle

55. Glycogen Function
•In liver –The synthesis and breakdown of glycogen is
regulated to maintain blood glucose levels.
•In muscle -The synthesis and breakdown of glycogen is
regulated to meet the energy requirements of the muscle cell.

56. Glycogenolysis
glycogen(n residues)+ Pi⇌glycogen(n-1 residues)+ glucose-1-
phosphate
•Here,glycogenphosphorylasecleavesthebondlinkingaterminal
glucoseresiduetoaglycogenbranchbysubstitutionof
aphosphorylgroupfortheα[1→4]linkage.Glucose-1-phosphateis
converted to glucose-6-phosphate by the
enzymephosphoglucomutase.Glucoseresiduesarephosphorolysed
frombranchesofglycogenuntilfourresiduesbeforeaglucosethat
isbranchedwithaα[1→6]linkage.

57. •Glycogendebranchingenzymethentransfersthreeofthe
remainingfourglucoseunitstotheendofanother
glycogenbranch.Thisexposestheα[1→6]branching
point,whichishydrolysedbyα[1→6]glucosidase,
removingthefinalglucoseresidueofthebranchasa
moleculeofglucoseandeliminatingthebranch.Thisisthe
onlycaseinwhichaglycogenmetaboliteisnotglucose-1-
phosphate.Theglucoseissubsequentlyphosphorylatedto
glucose-6-phosphatebyhexokinase.

59. •Theprocessiscausedbythehormonesglucagonand
epinephrinewhichstimulateglycogenolysisandwhich
areproducedinresponsetolowbloodglucoselevels.It
takesplaceinthemuscleandlivertissuewhichiswhere
glycogenisstored.

60. Control and regulations
Glycogenesisrespondstohormonalcontrol.Oneofthe
mainformsofcontrolisthevariedphosphorylationof
glycogensynthaseandglycogenphosphorylase.Thisis
regulatedbyenzymesunderthecontrolofhormonal
activity,whichisinturnregulatedbymanyfactors.As
such,therearemanydifferentpossibleeffectorswhen
comparedtoallostericsystemsofregulation.

61. •Epinephrinenot onlyactivatesglycogen
phosphorylasebutalsoinhibitsglycogensynthase.This
amplifiestheeffectofactivatingglycogenphosphorylase.
Thisinhibitionisachievedbyasimilarmechanism,as
proteinkinaseAactstophosphorylatetheenzyme,which
lowersactivity.Thisisknownasco-ordinatereciprocal
control.

62. •Insulinhasanantagonisticeffecttoepinephrinesignaling
viathebeta-adrenergicreceptor(G-Proteincoupled
receptor).Wheninsulinbindstoitsreceptor(insulin
receptor),itresultsintheactivation(phosphorylation)of
AktgenewhichinturnactivatesPhosphodiesterase(PDE).
PDEthenwillinhibitcyclicAMP(cAMP)actionandcause
inactivationofPKAwhichwillcauseHormoneSensitive
Lipase(HSL)tobedephosphorylatedandinactivesothat
lipolysisandlipogenesisisnotoccurringsimultaneously.

63. •CalciumionsorcyclicAMP(cAMP)actassecondary
messengers.Thisisanexampleofnegativecontrol.The
calciumionsactivatephosphorylasekinase.Thisactivates
glycogenphosphorylaseandinhibitsglycogensynthase.

64. •Carbohydrate Homeostasis
Brain and other nervous tissues,
except in long-term fasting use glucose as the sole energy source;
even in long-term fasting they require significant amounts of
glucose. Red blood cells can obtain energy only by anaerobic
glycolysis. Skeletal muscle at rest uses predominantly fatty acids,
but in heavy exercise it also draws on muscle glycogen and blood
glucose. Because brain and red blood cells depend on glucose for
energy, glucose must always be available.

65. •Glucose occurs in plasma and interstitial fluid at a concentration
of approximately 80 mg/dL. Approximately 180 g of glucose is
oxidized per day. The body must therefore replenish the total
blood glucose concentration about nine times a day;
nevertheless, the concentration in blood remains remarkably
constant. The glucose level following an overnight fast is
approximately 80 mg/dL. Following a meal, such as breakfast,
the level rapidly rises by 30-50 mg/dL, but within 2 hours it
returns to the previous level where it remains until the next
meal when the pattern is repeated. The remarkable stability of
the blood glucose level is an indication of the balance between
supply and utilization.

66. •Carbohydrate as a Food
•Carbohydrate is essential for the survival of some tissues and as
a structural constituent of nucleic acids, glycoproteins,
proteoglycans, and glycolipids. The normal adult can synthesize
all the needed carbohydrate from non-carbohydrate sources,
namely, amino acids and glycerol. Thus, humans can exist with
little or no dietary carbohydrate intake.
•Our normal diet generally consists of approximately 45%
carbohydrate, 43% lipid, and 10% protein. Of the carbohydrate,
about 60% is starch, 30% sucrose, and most of the remainder
lactose.

67. •Bloodsugarregulationistheprocessbywhichthelevels
ofbloodsugar,primarilyglucose,aremaintainedbythe
bodywithinanarrowrange.Thistightregulationis
referredtoasglucosehomeostasis.Insulin,whichlowers
bloodsugar,andglucagon,whichraisesit,arethemost
wellknownofthehormonesinvolved,butmorerecent
discoveriesofotherglucoregulatoryhormoneshave
expandedtheunderstandingofthisprocess.

68. Glucagon
Ifthebloodglucoselevelfallstodangerouslevels(asduring
veryheavyexerciseorlackoffoodforextendedperiods),
thealphacellsofthepancreasreleaseglucagon,
ahormonewhoseeffectsonlivercellsacttoincreaseblood
glucoselevels.Theyconvertglycogenintoglucose(this
processiscalledglycogenolysis).Theglucoseisreleasedinto
thebloodstream,increasingbloodsugar.

69. •GLUCAGON:Secretion of glucagon is stimulated by fall in
blood sugar level. Glucagon is antagonistic to insulin and
increases the blood sugar, lower the liver glycogen and may even
produce glucosuria because of its following effects.
(a)Glucagon enhances glycogenolysis in the liver.
(b)It increases hepatic gluconeogenesis.
(c)It decreases hepatic glycogenesis and thus reduces the removal
of blood glucose by the liver.

70. Hypoglycemia,thestateofhavinglowbloodsugar,istreated
byrestoringthebloodglucoseleveltonormalbythe
ingestionoradministrationofdextrose or
carbohydratefoods.Itisoftenself-diagnosedandself-
medicatedorallybytheingestionofbalancedmeals.Inmore
severecircumstances,itistreatedbyinjectionorinfusionof
glucagon.

71. Insulin
Whenlevelsofbloodsugarrise,whetherasaresult
ofglycogenconversion,orfromdigestionofameal,a
differenthormoneisreleasedfrombetacellsfoundin
theIsletsofLangerhansinthepancreas.This
hormone,insulin,causesthelivertoconvertmoreglucose
intoglycogen(thisprocessiscalledglycogenesis),andto
forceabout2/3ofbodycells(primarilymuscleandfattissue
cells)totakeupglucosefromthebloodthrough
theGLUT4transporter,thusdecreasingbloodsugar.

72. Wheninsulinbindstothereceptorsonthecellsurface,
vesiclescontainingtheGLUT4transporterscometothe
plasmamembraneandfusetogetherbytheprocessof
endocytosis,thusenablingafacilitateddiffusionofglucose
intothecell.Assoonastheglucoseentersthecell,itis
phosphorylatedintoGlucose-6-Phosphateinorderto
preservetheconcentrationgradientsoglucosewillcontinue
toenterthecell.Insulinalsoprovidessignalstoseveralother
bodysystems,andisthechiefregulatorofmetaboliccontrol
inhumans.

73. •A rise in blood sugar level stimulates insulin secretion. Insulin
lowers the blood sugar in several ways.
(a)It increases glucose uptake by muscles, adipocytes and other
extrahepatic tissues.
(b)It enhances utilization of glucose by promoting glycolysis and
aerobic metabolism of pyruvate in tissues and also by
stimulating lipogenesis from glucose in adipocytes.
(c)It decreases both glycogenolysis and gluconeogenesis in the liver
and there by decreases the addition of glucose to the blood.
(d)It stimulates glycogenesis in the liver to enhance the storage of
carbohydrates as liver glycogen.

74. Therearealsoseveralothercausesforanincreaseinblood
sugarlevels.Amongthemarethe'stress'hormonessuch
asepinephrine(alsoknownasadrenaline),severalofthe
steroids,infections,trauma,andofcourse,theingestionof
food.

75. Diabetesmellitustype1iscausedbyinsufficientornon-
existentproductionofinsulin,whiletype2isprimarilydue
toadecreasedresponsetoinsulininthetissuesofthebody
(insulinresistance).Bothtypesofdiabetes,ifuntreated,
resultintoomuchglucoseremainingintheblood
(hyperglycemia)andmanyofthesamecomplications.Also,
toomuchinsulinand/orexercisewithoutenough
correspondingfoodintakeindiabeticscanresultinlow
bloodsugar(hypoglycemia).

77. Clinical Correlates
A Glycogen storage disease (GSD,
alsoglycogenosisanddextrinosis)isametabolic
disordercausedbyenzymedeficienciesaffecting
eitherglycogensynthesis,glycogenbreakdown
orglycolysis(glucosebreakdown),typically
withinmusclesand/orlivercells.

78. •GSDhastwoclassesofcause:geneticandacquired.
GeneticGSDiscausedbyanyinbornerrorof
metabolism(geneticallydefectiveenzymes)involvedin
theseprocesses.Inlivestock,acquiredGSDiscaused
byintoxicationwiththealkaloidcastanospermine.

81. •Thisinabilitytomaintainadequatebloodglucoselevels
duringfastingresultsfromthecombinedimpairmentof
bothglycogenolysisandgluconeogenesis.
•Fastinghypoglycemiaisoftenthemostsignificant
probleminGSDI,andtypicallytheproblemthatleadsto
thediagnosis.

82. •Fastinghyperglycemiaisdefinedaswhenyoudon'teat
foratleasteighthours.Recommendedrangewithout
diabetesis70to130mg/dL.(Thestandardformeasuring
bloodglucoseis"mg/dL"whichmeansmilligramsper
deciliter.)Ifyourbloodglucoselevelisabove130mg/dL,
that'sfastinghyperglycemia.
•Becausefastingcanelevatecortisollevels.Oneof
cortisol'seffectsisthatitraisesbloodsugar.So,in
someonewithbloodsugarregulationissues,fastingcan
actuallymakethemworse.

83. •Hypoglycemiaistheconditionwhenyourbloodglucose
(sugar)levelsaretoolow.Ithappenstopeoplewith
diabeteswhentheyhaveamismatchofmedicine,food,
and/orexercise.Reactivehypoglycemia,whichhappens
withinafewhoursofeatingameal.Fasting
hypoglycemia,whichmayberelatedtoadisease