402

SECTION FOUR / FUEL OXIDATION AND THE GENERATION OF ATP

Resumo do Captulo 22 do Marks Glucose - Produo de ATP ATPPartir de two triose phosp twice by a and cleaved into diture in the beginning of the preparative phase Phase I: ATP Glicose: Gliclise Preparative pump, because this initial utilization of 2 mol
phase ATP

I.

in the production of 4 moles of ATP/mole o phase. Gliclise: Fructose 1,6 bisphosphate In the ATP-generating phase, glyceraldehyde A. Generalidades: oxidized by NAD and phosphorylated usin 1. Glicose: pode produzir ATP com ou sem O2 energy phosphate bond generated in this step is t 2 Triose phosphates 2. Produz piruvato, que pode ser oxidado a CO2 no Ciclo de Krebbsremaining phosphate is also rearranged to for e produzir ATP na Phase II: fosforilao oxidativa ATP generating (cadeia respiratria) bond that is transferred to ADP. Because there 2 NADH phase 3. Glicose armazenada nas clulas como glicognio 2 ATP formed, the yield from the ATP-generating phas 4. Gliclise tambm produz precursores para biossntese, como o piruvato, precurssor de ATP, 2 moles of NA is a net yield of 2 moles of 2 ATP mole of glucose. cidos graxos
2 Pyruvate B. Reaes da Gliclise: Fig. 22.3. Phases of the glycolytic pathway. 1. Fase preparatria: a) Converso de glicose a glicose-6-fosfato CH2OH O

1.

CONVERSION OF GLUCOSE TO GLUCOS

HO OH H

H OH OH

Glucose ATP ADP

hexokinase glucokinase (liver)

CH2OPO3 O

HO OH H

H OH OH

Glucose metabolism begins with transfer of a form glucose-6-P (Fig. 22.4). Phosphorylation o within the cell because glucose-6-P cannot be t membrane. The phosphorylation reaction is irr tions because the reaction has a high negative however, commit glucose to glycolysis. Glucose-6-P is a branchpoint in carbohydrat almost every pathway that uses glucose, includin pathway, and glycogen synthesis. From the opp generated from other pathways of carbohydrate sis (breakdown of glycogen), the pentose phosp (the synthesis of glucose from non-carbohydrate Hexokinases, the enzymes that catalyze the family of tissue-specific isoenzymes that diff isoenzyme found in liver and cells of the pa other hexokinases and is called glucokinase. In is bound to porins in the outer mitochondrial m channels; see Chapter 21), which gives these en sized ATP as it exits the mitochondria.
2.

Glucose 6 P Other Glycolysis pathways Pentose phosphate pathway Glycogen synthesis

CONVERSION OF GLUCOSE-6-P TO THE

In the remainder of the preparative phase of gly to fructose 6-phosphate (fructose-6-P), again cleaved into two 3-carbon fragments (Fig 22.5). Fig. 22.4. Glucose 6-phosphate metabolism. a keto group next to carbon 3, is essential for th (1) Inicia-se com a transferncia de um fosfato de ATP para a glicose, formando between carbons 3 and 4. glicose-6-fosfato, que no passa pela membrana plasmticanext reao local e phosphorylatio The --> step of glycolysis, irreversvel Hexokinases, other kinases, and bisphosphate (fructose-1,6-bisP) by phosphofru many other enzymes that catalyze (2) Glicose-6-Fosfato s produzida a partir da glicose considered the first committed step of the pathw reactions involving the hydrolysis (3) Enzimas: ATP and is thermodynamically and kinetically i of ATP require Mg2 . The Mg2 forms a com(a) Glicoquinase: with the phosphate groupsmuito alto ocably commits glucose to the glycolytic pathw s existe no fgado. Km of ATP. plex cells, and its regulation controls the entry of gl (b) Hexoquinase: outros tecidos. Km mais baixo Kinases also require K . nase, it exists as tissue-specific isoenzymes who (4) SALDO ATP: -1 ations in the role of glycolysis in different tissue b) Converso de glicose-6-fosfato em triose-fosfato Fructose-1,6-bisP is e (1) Isomerizao de glicose-6-Fosfato em frutose-6-fosfato, que fosforiladacleaved into two pho (triose phosphates) by aldolase (see Fig. 22 quebrada em triose-fosfato (DHAP) is isomerized to glyceraldehyde 3-phos is a triose phosphate. Thus, for every mole of g of glyceraldehyde-3-P continue through the path

CHAPTER 22 / GENERATION OF ATP FROM GLUCOSE: GLYCOLYSIS

403

(2) Ao da fosfo-glicoseisomerase :
O H H HO H H C C C C C OH H OH OH
hexokinase (glucokinase in liver)

O H ATP ADP H HO H H C C C C C OH H OH OH
phosphoglucose isomerase

CH2OH C HO H H C C C O H OH OH

Portion isomerized from aldehyde to keto sugar

CH2OH
D Glucose

2 CH2OPO3

CH2OPO3

Reposicionamento da carbonila em funo cetona, nico composto que pode ter a ligao entre C3 e C4 quebrada.
403

OF ATP FROM GLUCOSE: Glucose CHAPTER 22 / GENERATIONFructose 6 phosphate GLYCOLYSIS 6 phosphate

ATP (3) Fosforilao de F6F em frutose-1,6-difosfato:

O H OH H OH OH
hexokinase (glucokinase in liver)

O C C C C C OH H OH OH
2

phosphofructokinase 1

CH2OH C HO H C C
phosphoglucose isomerase

ATP

ADP

H HO H H

O H

H2OH

CH2OPO3

cose

Glucose 6phosphate

O H H C C OH

C from aldehyde O C O to keto sugar ATP ADP Aldol HO C H aldolase HO C H HO cleavage C H H C OH hexokinase phosphoglucose H C OH H C OH (glucokinase isomerase H C OH in liver) H C OH H C OH 2 CH2OPO3 2 CH2OPO3 CH2OPO3 Fructose Glucose 6 phosphate Fructose 6 phosphate 1,6bisphosphate

Etapa que determina que a Dihydroxyacetone a rota da Glicose-6-Fosfato seguirtriose Aldol HO C H phosphate phosphate aldolase isomerase cleavage gliclise, pois irreversvel H C OH H C OH O 2 Enzima fosfofrutoquinase-1: CH2OPO3 H C OH H pelas celulas C Regulada Fructose 6phosphate 2 CH2OPO3 Controla entrada de glicose na H C OH ATP 2 gliclise CH2OPO3 Fructose 403 CHAPTER 22 / GENERATION OF ATP FROM GLUCOSE: GLYCOLYSIS phosphofructokinase 1 1,6 bisphosphate Existem isoenzimas em outros 2 Glyceraldehyde CH2OPO3 ADP tecidos, em funo da 3 phosphate C O necessidade de gliclise 2 Pi CH2OPO3 CH2SALDO ATP: -2 glyceraldehyde CH2OH Portion isomerized OH +
OH
C O NAD 3 phosphate Dihydroxyacetone triose dehydrogenase NADH + H+ phosphate phosphate
isomerase

PortionADP isomerized from aldehyde to keto sugar 2 CH2OPO3

CH2OPO3 C O

CH2OH

O H H C C

High energy acyl-phosphate

O C ~ OPO3 C OH
2 2

OH

2 CH2OPO3

CH2OPO3

(4)

O C C CH3 Pyruvate O O
pyruvate kinase

ATP ADP

Glyceraldehyde 1,3 Bisphosphoglycerate 3phosphate Quebra de F1,6DF em triose-fosfatos: ADP phosphofructokinase 1 phosphoglycerate 2 P CH2iOPO3 kinase glyceraldehyde High energy ADP NAD+O 3phosphate ATP enolic phosphate C dehydrogenase 2 + CH2OPO3 O O NADH + H OH O CH2 mol H2O C O C O C 1 O de glicose C Dihydroxyacetone triose High energy O 2 2 i 2 Aldol phosphate C ~ OPO3 HO C H H acyl-phosphate C ~ OPOphosphateH C OH aldolaseC OPO3 3 isomerase cleavage enolase phosphoglycero 2 i CH2OH CH2OPO3 CH2 H C OH H C mutase OH O V
ATP

Phosphoenol - H pyruvate

OH 2 Phosphoglycerate H C

2 CH2OPO3

CH2OPO3
2

3 Phosphoglyceratetriose 2 mol de

CH2OPO3 ADP 1,6 bisphosphate phosphoglycerate Glyceraldehyde kinase High energy 3 phosphate ATP enolic phosphate for the mechanism of the forward reaction, which is an aldol cleavage, and the mechanism of the Aldolase is named Pi ATP: O 2. Fase formadora de O reverse reaction, which is an aldol condensation. The enzyme exists as O tissue-specific isoenzymes, which all catalyze the glyceraldehyde cleavage offructose 1,6-bisphosphate but differ in their specificities for C O 1-P. The enzyme uses a lysine residue at fructose NAD+ 3 phosphate H2O C O C O ATP ADP the active site to form a covalent bond with the substrate during the course ofdehydrogenase Inability to form this covalent linkage the reaction. + 2 2 NADH + H C ~ OPO H C OPO3 H C OH inactivates the enzyme.3 pyruvate enolase phosphoglycero 2 CH2OH CH2OPO3 CH2 kinase mutase High energy O

Fig. 22.5. Reactions of glycolysis. High-energy phosphates are shown in blue. Fructose

H C OH 1,3Bisphosphoglycerate

Phosphoenolpyruvate

2 C ~ OPO3 2Phosphoglycerate acyl-phosphate 3Phosphoglycerate

OH
2

ions of glycolysis. High-energy phosphates are shown in blue.

CH2OPO3

1,3 Bisphosphoglycerate

ADP se is named for the mechanism of the forward reaction, which is an aldol cleavage, and the mechanism of the phosphoglycerate e reaction, which is an aldol condensation. The enzyme exists as tissue-specific isoenzymes, which all catalyze the kinase High energy ATP ge of fructose 1,6-bisphosphate but differ in their specificities for fructose 1-P. The enzyme uses a lysine residue at enolic phosphate

ATP
phosphofructokinase 1

ADP CH2OPO3 Aldol a) Oxidao e fosforliao em nvel de substrato: C HO H C C O H OH

2 3 2

CH2OPO3 C O

CH2OH Dihydroxyacetone phosphate O

triose phosphate isomerase

cleavage

aldolase

H C OH H C (1) Enzima gliceraldedo-3-fosfato CH OPO H C OH desidrogenase: transfere e- do gliceraldedo Fructose CH OPO para NAD+, formando NADH e formaacil1,6 bisphosphate Glyceraldehyde fosfato de alta energia, que doa seu P para 3 phosphate ADP, formando ATP (ao da fosfoglicerato P glyceraldehyde NAD 3 phosphate quinase). dehydrogenase NADH + H (2) P do 3-fosfoglicerato pouco reativo --> transferido para C2 High energy O acyl-phosphate C ~ OPO (3) Piruvato-quinase transfere P para ADP, H C OH formando ATP CH OPO (4) SALDO ATP: +2 (tudo ocorre x2) 1,3 Bisphosphoglycerate
2 2 2 3 i + + 2 3 2 2 3

ADP High energy enolic phosphate O C C CH3 Pyruvate O O

pyruvate kinase

ATP O O O
2

phosphoglycerate kinase

O ATP ADP C O
2

H2O H
enolase

C C

C H
phosphoglycero mutase

C ~ OPO3 CH2

OPO3

OH
2

CH2OH 2 Phosphoglycerate

CH2OPO3

Phosphoenol pyruvate

3 Phosphoglycerate

Fig. 22.5. Reactions glicoltica: b) Resumo da rota of glycolysis. High-energy phosphates are shown in blue.
Aldolase is NADH: C. Destino do piruvato e do named for the mechanism of the forward reaction, which is an aldol cleavage, and the mechanism of the reverse reaction, which is an aldol condensation. The enzyme exists as tissue-specific isoenzymes, which all catalyze the 1. O NADH produzido precisa 1,6-bisphosphate but differ in their specificities for fructoseNAD+ para uses a lysine inibio cleavage of fructose ser continuamente reconvertido em 1-P. The enzyme impedir residue at the active por excesso desite to form a covalent bond with thea gliclise. 2 vias para reaction. Inability to form this ocorra: produto, o que pararia substrate during the course of the que a reconverso covalent linkage inactivates the enzyme. a) Aerbica: transfere, por meio de lanadeiras, o NADH para a mitocndria (membrana mitocondrial impermevel NADH), onde o H+ liberado para reagir com O2 b) Anaerbica: reoxidao de NADH pela lactato-desidrogenase,ATP FROM GLUCOSE: GLYCOLYSISa 405 CHAPTER 22 / GENERATION OF que reduz piruvato lactato.

Glicose + 2NAD+ +2P + 2ADP --> 2 Piruvato + 2 NADH + 4H+ +2 ATP + 2H2O

A. Aerobic glycolysis
Glucose 2 ADP + 2Pi 2 ATP 2 NAD+ XH2 Glycerol 3 P and Malate aspartate shuttles Electron transport chain O2 H2O ADP + Pi ATP

B. Anaerobic glycolysis
Glucose 2 ADP + 2Pi 2 ATP 2 NAD+

2 NADH+ + 2H+ 2 Pyruvate Acetyl CoA TCA cycle NADH CO2

2 NADH+ + 2H+ 2 Pyruvate 2 Lactate Lactate dehydrogenase

FAD(2H)

Mitochondrion

Fig. 22.6. Alternate 2. O piruvato pode: fates of pyruvate. A. The pyruvate produced by glycolysis enters mitochondria and is oxidized to CO and H O. The reducing equivalents in NADH enter mitochondria via a shuttle system. B. Pyruvate is reduced to lactate in the cytosol, thereby using the reducing a) Ser reduzido a lactato em ausncia de oxignio equivalents in NADH. b) Continuar a ser oxidado a acetil-CoA, entrar no ciclo de Krebbs e ser oxidado a CO2 to NADH, and no transport protein exists 3. Lanadeira de glicerol 3-fosfato:that can directly translocate NADH across this membrane. Consequently, NADH is reoxidized to NAD in the cytosol by a a) Lanadeira principal na maioria dos tecidos reaction that transfers the electrons to DHAP in the glycerol 3-phosphate (glycerol3-P) shuttle and oxaloacetate in + malateaspartate shuttle. The NAD that b) Reao: NADHcitosol + H+the FADmitocndria --> NAD+citosol +isFAD2Hmitocndria formed the c) Produzin1,5 cytosolde ATP/NADHtransferred across the inner mitochondrial mol returns to glycolysis while glycerol-3-P or malate carry the Glucose Pyruvate reducing equivalents that are ultimately 4. Lanadeira de malato-aspartato: membrane. Thus, these shuttles transfer electrons and not NADH per se. NAD NADH + H a) NADH oxidado pela ao do oxaloacetato (formado pela reao do aspartato), que Cytosolic 1. GLYCEROL 3PHOSPHATE SHUTTLE glycerol-3-P dehydrogenase convertido em malato is the major shuttle in most tissues. In this shuttle, The glycerol 3phosphate shuttle b) Produz 2,5 mol de ATP/NADH glycerol 3-phosphate dehydrogenase, Glycerol 3 P Dihydroxyacetone P cytosolic NAD is regenerated by cytoplasmic which transfers electrons from NADH to DHAP to form glycerol 3-phosphate (Fig. D. Gliclise anaerbica: 22.7). Glycerol 3-phosphate then diffuses through Mitochondrial Inner 1. Produz 2 to the inner mitochondrial membrane, where the outer mitochondrial memATP enquanto aerbica pode produzir 32 ATP (dependendo da lanadeira) glycerol-3-P brane the electrons are donated to a
2 2

membrane-bound flavin adenive dinucleofide (FAD)-containing glycerophosphate dehydrogenase. This enzyme, like succinate dehydrogenase, ultimately donates electrons to CoQ, resulting in an energy yield of approximately 1.5 ATP from oxidative phosphorylation. Dihydroxyacetone phosphate returns to the cytosol to continue the shuttle. The sum of the reactions in this shuttle system is simply:

mitochondrial membrane

dehydrogenase

FAD

FAD (2H)

Electron transport chain

Fig. 22.7. Glycerol 3-phosphate shuttle.

2. Necessidade de glclise anaerbica gasta reservas de glicognio da clula em funo da grande demanda de Glicose-6-Fosfato 3. Produz cido ltico, que se dissocia em lactato, H+ e carboxilato. Lactato e H+ so transportados para a corrente sangunea e podem causar distrbios no tampo sanguneo 4. Tecidos dependendentes da gliclise anaerbica: a) Eritrcitos (no tm mitocndrias) e leuccitos b) Tecidos com baixa demanda de ATP, alta concentrao de enzimas glicolticas e pouco irrigados 5. Destino do lactato: a) Metabolizado por outros tecidos, como o fgado e o corao b) Reao: lactato + NAD+ --> Piruvato + NADH + H+ E. Outras funes da gliclise: 1. Intermedirios do processo podem ser convertidos em ribose 5-fosfato, acar incorporado ao ATP, UDP-glicose, manose e cido silico 2. Serina pode ser sintetizada a partir de 3-fosfoglicerato 3. Alanina pode ser sintetizada a partir do piruvato 4. O fgado sintetiza cidos graxos a partir de piruvato, glicose a partir de lactato, CHAPTER 22 / GENERATION OF ATP FROM GLUCOSE: GLYCOLYSIS glicerol-3-fosfato e aminocidos.
Glucose 5 carbon sugars

Glucose-6-P Glycerol P 1,3 bisphosphoglycerate Triglyceride Fatty acids

2,3 bisphosphoglycerate Serine Alanine 3-phosphoglycerate Pyruvate

Acetyl CoA TCA cycle

Glutamate and other amino acids

Fig. 22.11. Biosynthetic functions of das necessidades formed F. Regulao da gliclise em funo glycolysis. Compoundsde ATP:from intermediates of 1. glycolysis are reguladablue. These pathwayshomeostasein subsequent chapters of the Gliclise shown in para manter a are discussed de ATP nas clulas 2. book. Dotted lines indicate thatpiruvato one step is required enzimas que ligam ain Fosfofrutoquinase-1 e more than desidrogenase, for the conversion shown gliclise ao ciclo de the figure. Krebbs, so enzimas que respondem ao mecanismo de feed-back da quantidade de ATP que utilizada pela clula 3. enzyme phosphoglyceromutase. Because 2,3-BPG pode ser regulada pelain this Quantidade de glicose-6-fosfato na clula is not depleted by its role quantidade de glicose catalytic process, most cells need only very small amounts. transportada para dentro na clula, pela quebra de glicognio 4. Relao entre concentrae sde ATP, ADP e AMP: III. REGULATION OF GLYCOLYSIS BY THEum indicador ATP a) A concentrao de AMP no citoplasma NEED FOR da taxa de utilizao de ATP (1) Reao: 2 ADP = glycolysis is One of the major functions of AMP + ATP the generation of ATP, and, therefore, (2) ATP est presente em ATP homeostasis in maiores no citoplasma --> equilbrio the pathway is regulated to maintainquantidades muitoall cells. Phosphofructokinase-1 deslocado para a esquerda e, portanto, as concentraes de AMP so muito (PFK-1) and pyruvate dehydrogenase (PDH), which links glycolysis baixas. Dessa maneira, pequenas variaes na concentrao and the TCA cycle, are both major regulatory sites that respond to feedback indi- de ATP causam grandes variae na concentrao de supply cators of the rate of ATP utilization (Fig. 22.12). The AMP of glucose-6-P for

glycolysis is tissue dependent and can be regulated at the steps of glucose transport into cells, glycogenolysis (the degradation of glycogen to form glucose), or the rate of glucose phosphorylation by hexokinase isoenzymes. Other regulatory mechanisms integrate the ATP-generating role of glycolysis with its anabolic roles.

(3) O AMP ativa diversas vias metablicas, como a prpria gliclise 5. Regulao da hexoquinase: a) Na maioria dos tecidos, a hexoquisase tem um Km baixo e alta anidade pela glicose. Ela inibida por altas concentraes de glicose-6-fosfato. b) No fgado, a glicoquinase tem alto Km e no prontamente inibida por altas concentraes de glicose-6-fosfato 6. Regulao da fosfofrutoquinase-1: a) Enzima que controla a entrada de glicose-6-fosfato na gliclise b) Enzima alostrica com 6 stios ativos, 2 para substratos e 4 para reguladores alostricos (inibem ou ativam a enzima, mudando a conformao espacial dos outros 2 stios). Inibitrios: MgATP, citrato. Ativadores: AMP, frutose-2,6-difosfato 7. Regulao da piruvato-quinase: a) Tem diferentes tipos nos tecidos. b) Crebro: no tem stios ativos, portanto, no participa na regulao da gliclise 8. Regulao da piruvato-desidrogenase e da gliclise: a) Enzima regulada pela taxa de consumo de ATP b) Inibida por NADH G. Acidose ltica: 1. No indivduo saudvel, altas concentraes de lactato no sangue so associadas com gliclise anaerbica durante atividade fsica. 2. Na acidose ltica, o cido acumula no sangue e afeta o pH 3. resultado de um aumento na quantidade de NADH nos tecidos, o que inibe a oxidao do piruvato pela piruvato-desidrogenase