-탄수화물 대사의 주요회로(그림8.1) 8.1 해당작용 -혐기성생물: 해당과정 이용 (EMP 회로로도 불림) -호기성호흡: 피르브산을 CO2, H2O로 산화 (1)해당경로의 반응(그림8.2): 양반응회로 (이화와 동화) 글루코오스-6-인산의 합성(그림) 글루코오스-6-인산의 프룩토오스-6-인산으로의 전환 프룩토오스-6-인산의 인산화; 포스포프룩토키나제-1은 주요 조절효소 -다른자리입체성 활성제(AMP), 억제제(ATP, 시트르산) 4. 프룩토오스-1,6-이인산의 절단:알돌절단 5. 글리세르알데히드-3-인산과 디히드록시아세톤인산의 상호전환 6. 글리세르알데히드-3-인산의 산화 글리세르알데히드-3-인산 탈수소효소(GAPDH)는 기질과 티오에스테르결합을 하면서 수소화이온을 활성자리에 있는 NAD+에 전이함(그림8.3) 7. 인산기전이 -기질수준인산화; 높은 인산기 전이전위를 갖는 기질에서 ATP합성

Chapter 8 Carbohydrate Metabolism Overview Metabolism and Jet Engines Section 8.1: Glycolysis Section 8.2: Gluconeogenesis Section 8.3: The Pentose Phosphate Pathway Section 8.4: Metabolism of Other Important Sugars Section 8.5: Glycogen Metabolism From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Chapter 8: Overview Figure 8.1 Major Pathways in Carbohydrate Metabolism Energy transforming pathways of carbohydrate metabolism include glycolysis, glycogenesis, glycogenolysis, gluconeogenesis, and pentose phosphate pathway From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Glycolysis (anaerobic process) occurs in almost every living cell Section 8.1: Glycolysis Figure 8.1 Major Pathways in Carbohydrate Metabolism Glycolysis (anaerobic process) occurs in almost every living cell Ancient process central to all life Splits glucose into two three-carbon pyruvate units Catabolic process that captures some energy as 2 ATP and 2 NADH From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Glycolysis is an anaerobic process Section 8.1: Glycolysis Glycolysis is an anaerobic process Two stages (stage 1 and 2): energy investment and energy producing Glycolytic Pathway: D-Glucose + 2 ADP + 2 Pi + 2 NAD+  2 pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.1: Glycolysis Figure 8.2 Glycolytic Pathway From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.1: Glycolysis Figure 8.2 Glycolytic Pathway From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Reactions of the Glycolytic Pathway Section 8.1: Glycolysis Reactions of the Glycolytic Pathway 1. Synthesis of glucose-6-phosphate Phosphorylation of glucose (kinase) prevents transport out of the cell and increases reactivity 2. Conversion of glucose-6-phosphate to fructose-6-phosphate Conversion of aldose to ketose Figure 8.2a Glycolytic Pathway From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Reactions of the Glycolytic Pathway Continued Section 8.1: Glycolysis Reactions of the Glycolytic Pathway Continued 3. Phosphorylation of fructose-6-phosphate This step is irreversible due to a large decrease in free energy and commits the molecule to glycolysis 4. Cleavage of fructose-1,6-bisphosphate Aldol cleavage giving an aldose and ketose product Figure 8.2a Glycolytic Pathway From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Reactions of the Glycolytic Pathway Continued Section 8.1: Glycolysis Reactions of the Glycolytic Pathway Continued 5. Interconversion of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate Conversion of aldose to ketose enables all carbons to continue through glycolysis Figure 8.2a Glycolytic Pathway From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Reactions of the Glycolytic Pathway Continued Section 8.1: Glycolysis Reactions of the Glycolytic Pathway Continued In Step 2 (reactions 6-10), each reaction occurs in duplicate 6. Oxidation of glyceraldehyde-3-phosphate Creates high-energy phosphoanhydride bond for ATP formation and NADH 7. Phosphoryl group transfer Production of ATP via substrate-level phosphorylation Figure 8.2b Glycolytic Pathway (Stage 2) From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

8. 글리세린산-3-인산과 글리세린산-2-인산의 상호작용: 전환반응 9. 글리세린산-2-인산의 탈수반응(PEP생성) -엔올라제 -토토머라고도 불리는 케토와 엔올형의 상호전환을 토토머화라함 -해당과정 10개 반응도식(그림8.4) 10. 피루브산의 합성 (2)피르브산의 운명 -구연산회로 (탈카복실화 후에) -전자전달계; 산화환원반응, 양성자구배 -발효(그림8.5): 젖산(그림8.6)-호모젖산발효생물, 에탄올-헤테로젖산발효생물(), 탈카복실화, 부탄올 -포도주제조: 에틸아세트산, 아밀알코올, 티라민은 숙취유발 -맥주양조

Reactions of the Glycolytic Pathway Continued Section 8.1: Glycolysis Reactions of the Glycolytic Pathway Continued 8. Interconversion of 3-phosphoglycerate and 2-phosphoglycerate First step in formation of phosphoenolpyruvate (PEP) 9. Dehydration of 2-phosphoglycerate Production of PEP, which has a high phosphoryl group transfer potential (tautomerization), locks it into the highest energy form Figure 8.2b Glycolytic Pathway (Stage 2) From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Reactions of the Glycolytic Pathway Continued Section 8.1: Glycolysis Reactions of the Glycolytic Pathway Continued 10. Synthesis of pyruvate Formation of pyruvate and ATP Produces a net of 2 ATP, 2 NADH, and 2 pyruvate Figure 8.2b Glycolytic Pathway (Stage 2) From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.1: Glycolysis Figure 8.3Glyceraldehyde-3-Phosphate Dehydrogenase Reaction Oxidation of glyceraldehyde-3-phosphate (G-3-P) is a 2-step process (reaction 6) G-3-P undergoes oxidation and phosphorylation G-3-P interacts with the sulfhydryl group in the enzyme’s active site From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.1: Glycolysis Figure 8.3 Glyceraldehyde-3-Phosphate Dehydrogenase Reaction From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.1: Glycolysis Oxidation of glyceraldehyde-3-phosphate (G-3-P) is a complex process (reaction 6) Substrate oxidized after interaction with sulfhydryl Bound NADH exchanged for NAD+ Enzyme displaced by addition of inorganic phosphate From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.1: Glycolysis The Fates of Pyruvate Figure 8.5 The Fates of Pyruvate The Fates of Pyruvate Pyruvate is an energy-rich molecule Under aerobic conditions, pyruvate is converted to acetyl-CoA for use in the citric acid cycle and electron transport chain From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

The Fates of Pyruvate Continued Section 8.1: Glycolysis The Fates of Pyruvate Continued Under anaerobic conditions pyruvate can undergo fermentation: alcoholic or homolactic Regenerates NAD+ so glycolysis can continue Figure 8.6 Recycling NADH during Anaerobic Glycolysis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

(3)해당과정의 에너지론 -각 개별 반응의 표준자유에너지변화, 회로의 효율성(그림8.7) -가역적, 비가역적, 글루코오스신생 (4)해당작용의 조절 *육탄당 인산화효소 *다른자리입체성조절 -PFK-1과 피루브산키나아제 효소의 다른자리 입체성조절(그림8.8, 표8.1) *호르몬조절 *AMPK: A 대사의 주요 전환점 8.2 포도당 신생합성 -간에서 일어남, 혈당량조절; 대사산독증 및 기아시 신장에서 - 전구물질: 젖산, 피루브산, 글리세롤, α-케토산 등 포도당 신생합성 반응 -3개의 해당과정은 비가역적, 신생반응에서는 다른 효소로 극복 -그림8.9, 신생회로와 해당과정의 상관관계 포스포엔올피루브산의 합성 -피루브산 카르복실화효소(미토콘드리아의)와 -PEP 카르복시키나아제 ; OAA를 말산셔틀(말산탈수소효소사용)을 사용하여 세포질로 전이 (284p)

Energetics of Glycolysis Section 8.1: Glycolysis Figure 8.7 Free Energy Changes during Glycolysis in Red Blood Cells Energetics of Glycolysis In red blood cells, only three reactions have significantly negative DG values From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Regulation of Glycolysis Section 8.1: Glycolysis Regulation of Glycolysis The rate of the glycolytic pathway in a cell is controlled by the allosteric enzymes: Hexokinases I, II, and III PFK-1 Pyruvate kinase Allosteric enzymes are sensitive indicators of a cell’s metabolic state regulated locally by effector molecules The peptide hormones glucagon and insulin also regulate glycolysis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Regulation of Glycolysis Continued Section 8.1: Glycolysis Regulation of Glycolysis Continued High AMP concentrations activate pyruvate kinase Fructose-2,6-bisphosphate, produced via hormone- induced covalent modification of PFK-2, activates PFK-1 Accumulation of fructose-1,6-bisphosphate activates PFK-1 providing a feed-forward mechanism From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.1: Glycolysis Figure 8.8 Fructose-2,6-Bisphosphate Level Regulation From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.2: Gluconeogenesis Gluconeogenesis is the formation of new glucose molecules from precursors in the liver Precursor molecules include lactate, pyruvate, and a-keto acids Gluconeogenesis Reactions Reverse of glycolysis except the three irreversible reactions From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.2: Gluconeogenesis Figure 8.9 Carbohydrate Metabolism: Gluconeogenesis and Glycolysis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.2: Gluconeogenesis Figure 8.9 Carbohydrate Metabolism: Gluconeogenesis and Glycolysis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

2. 프룩토오스-1,6-이인산의 프룩토오스-6-인산으로의 전환 프룩토오스-1,6-이인산가수분해효소로 우회 3. 글루코오스-6-인산으로부터 글루코오스 합성 간, 신장에만 글루코오스-6-인산 가수분해효소존재 신생과 해당반응이 협동적으로 조절됨 (2)포도당 신생합성 기질 -코리회로에서 젖산은 운동 중 골격근육에 의해 방출된다(그림8.10) -운동하는 근육이 다량의 피루브산을 만들 때 일부는 아미노산 전이반응에 의해 알라닌으로 전환됨;글루코오스-알라닌회로(그림8.11) (3)포도당 신생합성 조절 -인슐린, 글루카곤 (그림8.12) (*글루코오스를 이용하는 뇌 -PET 스캔(그림))

Section 8.2: Gluconeogenesis Gluconeogenesis Reactions Continued Three bypass reactions: 1. Synthesis of phosphoenolpyruvate (PEP) via the enzymes pyruvate carboxylase and pyruvate carboxykinase 2. Conversion of fructose-1,6-bisphosphate to fructose-6-phosphate via the enzyme fructose-1,6-bisphosphatase 3. Formation of glucose from glucose-6-phosphate via the liver and kidney-specific enzyme glucose-6-phosphatase From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.2: Gluconeogenesis Gluconeogenesis Substrates Three of the most important substrates for gluconeogenesis are: 1. Lactate—released by skeletal muscle from the Cori cycle After transfer to the liver lactate is converted to pyruvate, then to glucose 2. Glycerol—a product of fat metabolism Figure 8.10 Cori Cycle From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.2: Gluconeogenesis Figure 8.11 The Glucose Alanine Cycle Gluconeogenesis Substrates Continued 3. Alanine—generated from pyruvate in exercising muscle Alanine is converted to pyruvate and then glucose in the liver From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.2: Gluconeogenesis Gluconeogenesis Regulation Substrate availability Hormones (e.g., cortisol and insulin) Figure 8.12 Allosteric Regulation of Glycolysis and Gluconeogenesis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.2: Gluconeogenesis + Gluconeogenesis Regulation Continued Allosteric enzymes (pyruvate carboxylase, pyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase) Figure 8.12 Allosteric Regulation of Glycolysis and Gluconeogenesis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

8.3 오탄당인산 회로 -ATP재생은 없으며, NADPH와 리보오스-5-인산가 주 생성물 -산화적(그림 8.13a) 및 비산화적단계 (그림 8.13b) -지질합성, 항산화작용 등 환원과정에 필요한 상당량의 NADPH합성이 일어남 NADPH는 강력한 항산화제 그림8.13b: 삼탄당, 오탄당, 육탄당의 상호전환 오탄당이 생합성반응에 사용되지 않을 때 비산화적단계의 대사물질은 해당과정의 중간물질로 전환되어 분해됨(그림8.14): 육탄당일인산회로도 명명 8.4 다른 중요한 당의 대사(그림8.15) 과당 대사 -두가지 경로로 해당과정에 들어감 ((2)갈락토오스대사 -갈락토오스-갈락토오스1인산; 갈락토오스1인산-UDP갈락토오스; UDP갈락토오스- UDP글루코오스; 글리코겐합성 혹은 글루코오스1인산 (3)만노오스대사: 프룩토오스6인산으로 전환)

Section 8.3: Pentose Phosphate Pathway Alternate glucose metabolic pathway Products are NADPH and ribose-5-phosphate Two phases: oxidative and nonoxidative Glucose-6-phosphate dehydrogenase Gluconolactonase Figure 8.13a The Pentose Phosphate Pathway (oxidative) From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.3: Pentose Phosphate Pathway 6-phosphogluconate dehydrogenase Pentose Phosphate Pathway: Oxidative Three reactions Results in ribulose-5-phosphate and two NADPH NADPH is a reducing agent used in anabolic processes Figure 8.13a The Pentose Phosphate Pathway (oxidative) From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.3: Pentose Phosphate Pathway Pentose Phosphate Pathway: Nonoxidative Produces important intermediates for nucleotide biosynthesis and glycolysis Ribose-5-phosphate Glyceraldehyde-3-phosphate Fructose-6-phosphate Figure 8.13b The Pentose Phosphate Pathway (nonoxidative) From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.3: Pentose Phosphate Pathway If the cell requires more NADPH than ribose molecules, products of the nonoxidative phase can be shuttled into glycolysis Figure 8.14 Carbohydrate Metabolism: Glycolysis and the Phosphate Pathway From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.4: Metabolism of Other Important Sugars Figure 8.15 Carbohydrate Metabolism: Galactose Metabolism Fructose, mannose, and galactose are also important sugars for vertebrates Most common sugars found in oligosaccharides besides glucose From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Fructose Metabolism Section 8.4: Metabolism of Other Important Sugars Second to glucose in the human diet Can enter the glycolytic pathway in two ways: Through the liver (multi-enzymatic process) Muscle and adipose tissue (hexokinase) From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.4: Metabolism of Other Important Sugars Figure 8.15 Carbohydrate Metabolism: Other Important Sugars From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

8.5 글리코겐대사 -분해 및 합성은 인슐린, 글루카곤, 에피네프린에 의해 조절 (1)글리코겐합성 글루코오스-1-인산의 합성 UDP-글루코오스의 합성; 글루코오스보다 반응성이 높다. UDP-글루코오스로부터 글리코겐 합성 -두 가지효소가 필요: 글리코겐합성효소(그림8.16a), α(1.6)결합분지효소[아밀로-α(1,4→1.6)-글루코실 전이효소](그림8.16b) (2)글리코겐분해 -두 반응을 필요: 글리코겐의 비환원말단으로부터 글루코오스제거(덱스트린형성까지 진행)(그림8.17), 글리코겐의 분지점에서 α(1.6)글리코시드 결합의 가수분해, 자유글루코오스형성(그림8.18) -요약(그림8.19) (3)글리코겐의 대사조절 -호르몬에 의해(인슐린, 글루카곤, 에피네프린) -아데닐산 시클라아제, cAMP(2차 전령), 인산화다단계반응 -그림8.20

Section 8.5: Glycogen Metabolism Glycogenesis Synthesis of glycogen, the storage form of glucose, occurs after a meal Requires a set of three reactions (1 and 2 are preparatory and 3 is for chain elongation): 1. Synthesis of glucose-1-phosphate (G1P) from glucose-6-phosphate by phosphoglucomutase 2. Synthesis of UDP-glucose from G1P by UDP-glucose phosphorylase From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.5: Glycogen Metabolism Figure 8.16a Glycogen Synthesis Glycogen synthase Glycogenesis Continued 3. Synthesis of Glycogen from UDP-glucose requires two enzymes: Glycogen synthase to grow the chain From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Glycogenesis Continued Section 8.5: Glycogen Metabolism Branching enzyme Glycogenesis Continued Branching enzyme amylo-a(1,41,6)-glucosyl transferase creates a(1,6) linkages for branches a(1,6) Glycosidic Linkage is formed Figure 8.16b Glycogen Synthesis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Glycogenolysis Section 8.5: Glycogen Metabolism Glycogen degradation requires two reactions: 1. Removal of glucose from nonreducing ends (glycogen phosphorylase) within four glucose of a branch point From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.5: Glycogen Metabolism Figure 8.17 Glycogen Degradation From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Glycogenolysis Cont. Section 8.5: Glycogen Metabolism Glycogen degradation requires two reactions: 2. Hydrolysis of the a(1,6) glycosidic bonds at branch points by amylo-a(1,6)-glucosidase (debranching enzyme) Amylo-a(1,6)-glucosidase Figure 8.19 Glycogen Degradation via Debranching Enzyme Amylo-a(1,6)-glucosidase From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.5: Glycogen Metabolism Amylo-a(1,6)-glucosidase Figure 8.18 Glycogen Degradation via Debranching Enzyme From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.5: Glycogen Metabolism Regulation of Glycogen Metabolism Carefully regulated to maintain consistent energy levels Regulation involves insulin, glucagon, epinephrine, and allosteric effectors Figure 8.20 Major Factors Affecting Glycogen Metabolism From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Section 8.5: Glycogen Metabolism Glucagon activates glycogenolysis Insulin inhibits glycogenolysis and activates glycogenesis Epinephrine release activates glycogenolysis and inhibits glycogenesis Figure 8.20 Major Factors Affecting Glycogen Metabolism From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Biochemistry in Perspective Saccharomyces cerevisiae and the Crabtree effect S. cerevisiae is the only yeast that can produce ethanol and CO2 in such large quantities S. cerevisiae ferments carbohydrates efficiently and dominates its environment due to the Crabtree effect The Crabtree Effect Unlike most fermenting organisms S. cerevisiae can also ferment sugar in the presence of O2 As glucose and/or fructose levels rise pyruvate is diverted away from the citric acid cycle into ethanol synthesis From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Biochemistry in Perspective The phenomenon, in which glucose represses aerobic metabolism, is the Crabtree effect Rapid production of ethanol has the effect of eliminating microbial competitors Once glucose levels are depleted and O2 is available the yeast reabsorbs the ethanol and converts it to acetaldehyde for use as an energy source From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press

Biochemistry in Perspective Figure 8A Ethanol Metabolism in S. cerevisiae From McKee and McKee, Biochemistry, International Fifth Edition, © 2012 by Oxford University Press