1. Carbohydrate metabolism
糖 代 谢
Carbohydrate metabolism

2. Section 1
Overview

4. Carbohydrates in general are polyhydroxy aldehydes or ketones or compounds which yield these on hydrolysis.

5. Biosignificance of Carbohydrates
Carbohydrates are the most abundant biomolecules on earth and have multiple roles in all forms of life.
Carbohydrates serve as energy stores (e.g., starch in plants, glycogen in animals), fuels (e.g., glucose), and metabolic intermediates (e.g., ATP, many coenzymes辅酶).
Carbohydrates serve as structural elements in cell walls of plants (cellulose) or bacteria (peptidoglycans), exoskeletons of arthropods (chitin), and extracellular matrixes of vertebrate animals (proteoglycans).

6. Carbohydrates serve as recognition signals in glycoproteins and glycolipids determining cell-cell recognition, intracellular location, and metabolic fates of proteins (thus sugars, like nucleic acids and proteins, are also information rich! But codes unknown).
Carbohydrates (ribose and deoxyribose) form part of the structural framework of RNA and DNA.

7. Cells Have Choice among Alternative Substrates, but Glucose Is more Important for Their Needs
The most important fuctions of carbohydrates
Generation of metabolic energy
Maintenance of a normal blood glucose level
Supply of specialized monosaccharides as biosynthetic precursors
Some sugar derivates are important bioactive compounds

8. Carbohydrates can be categorized into monosaccharides, oligosaccharides, and polysacchrides.
Monosacchrides单糖 are simple sugars consisting of a single polyhydroxyl aldehyde or ketone unit (e.g., glyceraldehyde, dihydroxyacetone, ribose, glucose, galactose, ribulose, and fructose).
Oligosaccharides低聚糖 contain two (disaccharides) or a few monosaccharides joined by glycosidic bonds (e.g., lactose, sucrose, maltose, some covalently linked sugars in glycoproteins and glycolipids).
甘油醛、二羟基丙酮、核糖、葡萄糖、半乳糖、核酮糖、果糖 乳糖、蔗糖、麦芽糖

9. Polysaccharides多糖 contain long chains of (hundreds to thousands) monosaccharide units joined by glycosidic bonds (e.g., glycogen, starch, cellulose, chitin, and glycosaminoglycans).
肝糖原、淀粉、纤维素、壳糖、粘多糖

10. Monosacchrides contain one carbonyl group and two or more hydroxyl groups.
Monosacchrides can be divided into two families: aldoses醛糖 and ketoses酮糖.
Aldoses have their carbonyl groups at the ends of the carbon chains, thus being an aldehyde.
Ketoses have their carbonyl groups at places other than the ends, thus being ketones.
The simplest aldose is glyceraldehyde, and the simplest ketose is dihyoxyacetone, both being triose丙糖或三糖.

12. Monosacchrides containing four, five, and six carbon atoms in their backbones are called tetroses, pentoses (e.g., ribose and deoxyribose), and hexoses (e.g., glucose and fructose), respectively.
Hexoses are the most common monosacchrides in nature, including D-glucose, D-mannose, D-galactose, D-fructose.

15. Glyceraldehyde is conventionally used as the standard for defining D and L configurations: D-glyceraldehyde has the -OH group on the right, L-glyceraldehyde has the -OH group on the left.

16. For sugars with more than one asymmetric carbon atom, the D- and L- symbols refer to the absolute configuration of the asymmetric carbon farthest to the carbonyl group (e.g., in D-fructose, the -OH on C-5 has the same configuration as the asymmetric carbon in D-glyceraldehyde, therefore, D- and L- glucoses are not enantiomers but stereoisomers!)

17. 对映体、镜像构造

18. The forms of monosaccharides predominate in nature, just as L-amino acids do.

20. Most of the monosaccharides found in living organisms are the D-isomers (e.g., D-ribose, D-glucose, D-galactose, D-mannose, D-fructose)
Each stereoisomer has a different conventional name, ending with “-ose” suffix.
Ketoses are often named by inserting an “ul” into the name of the corresponding aldoses (e.g., aldopentose is named as ribose, the ketopentose is named as ribulose.

25. Two sugars differing in configuration at a single asymmetric carbon is called epimers to each other (e.g., D-glucose and D-mannose are epimers at C-2; D-glucose and D-galactose are epimers at C-4).

26. An aldehyde can react with one alcohol to form a hemiacetal (two alcohol to form acetal), a ketone with an alcohol to form a hemiketal.
In the open chain form of glucose, the aldehyde group at C-1 and the hydroxyl group at C-5 react to form two six-membered pyran-like cyclic stereoisomers: the a-D-glucopyranose (the -OH group attached to C-1 locates on a different side from the C-6 atom) and the β-D-glucospyranose (-OH of C-1 on the same side of the plane as C-6), thus being specifically called anomers to each other.

27. Anomeric carbon
异端碳原子或异头碳

30. Monosaccharide units can link with each other through O-glycosidic bonds to form oligo- and polysaccharides.
Disaccharides consist of two monosaccharides linked through an O-glycosidic bond.
Sucrose, lactose and maltose are the most abundant disaccharides in nature.
In sucrose (common table sugar), the anomeric carbon of one a-D-glucose is joined to the hydroxyl oxygen atom on C-2 of an β-D-fructose.

33. Sucrose, lactose, and maltose can be abbreviated as Glc(α1-2β)Fru, (or Fru(β2-1a)Glc), Gal(β1-4)Glc, and Glc(α1-4)Glc, respectively.
Both lactose and maltose have a free anomeric carbon (not involved in glycosidic bond) that can be oxidized, thus being reducing sugars.
The end of an oligo- and polysaccharide having a free anomeric carbon is called the reducing end.
Sucrose does not have a reducing end (the anomeric carbons of both saccharide units are involved in glycosidic bond).

34. The three disaccharides can be hydrolyzed into two monosaccharide units by specific sucrase (also called invertase), lactase (β-galactosidase in bacteria), and maltase existing on the outer surface of epithelial cells lining of the small intestines. (milk allergy过敏 is due to lack of lactase in the intestines).

35. Glycogen and starch are mobilizable stores of glucose in animals and plants respectively.
Glycogen (mainly in liver and skeleton muscles) is a polymer of (a1-4) linked glucose units with (a1-6) linked branches (occurring about once every 10 glucose residues).
Starch can be linear or branched polymers of glucose, called amylose直链淀粉 and amylopectin支链淀粉, respectively.
Amylose consists of D-glucose residues in (a1-4) linkage.
Amylopectin has about one (a1-6) branch per 30 (a1-4) linkages.
Amylopectin is like glycogen except for its lower degree of branching.

36. Each amylose has one nonreducing one and one reducing one, but each amylopectin and glycogen has one reducing end and many nonreducing ends.
Starch and glycogen ingested in the diet are hydrolyzed by α-amylase (present in saliva and intestinal juice) that break the a1,4 glycosidic linkages between glucose units. (starting from the nonreducing ends). The end of an oligo- and polysaccharide having a free anomeric carbon is called the reducing end.

43. Cellulose and chitin are structural homopolysaccharides同聚多糖 with similar composition and structures.
Cellulose, like amylose, is a linear homopolysaccharide of 10,000 or 15,000 D-glucose residues, but with (β1-4) linkages.
Chitin is a linear homopolysaccharide composed of N-acetyl-D-glucosamine residues also with (β1-4) linkages.
The only chemical difference between cellulose and chitin is the replacement of a hydroxyl group at C-2 with an acetylated amino group.

44. Most animals lack enzymes to hydrolyze cellulose but some (like termites and ruminant animals) can use cellulose because of the cellulase secreted by symbiotic microorganisms.
The (β1-4) linkage allow the polysaccharide chains of cellulose and chitin to take an extended conformation forming parallel fibers through intrachain and interchain hydrogen bond.

47. chitin

48. Glucose Is the Principal Transported Carbohydrate in human
The most abundant monosaccharide in dietary carbohydrates is glucose.
Glucose Can be transported by blood
Glucose Cannot be stored in cells, only if it can be converted to glycogen
Blood glucose level

49. Glucose Uptake into the Cells Is Regulated
Glucose transporter
The glucose were absorbed by sodium-dependent glucose transporter (SGLT)
And then, they were take up by muscle, adipose tissue, brain and other tissue cells through glucose transporter(GLUT)
Intestinal cavity of small intestine
Intestinal epithelium cells
portal
liver
Systemic circulation
SGLT
Various tissue cells
GLUT

50. Glucose transporters (GLUT)
GLUT1: RBC
GLUT4: adipose tissue, muscle

51. Glucose Oxidation Can Proceed in Many Different Pathway
Glucogen
glycogenolysis
glycogenesis
ATP
H2O,CO2
pentose phosphate pathway
Ribose +
NADPH+H+
aerobic
glycolysis
Glucose
Pyruvate
anaerobic
digestion,
absorbtion
gluconeogenesis
Lactic acid
Starch
Lactic acid,amino acid,glycerol

52. The metabolism of glucose
glycolysis
aerobic oxidation
pentose phosphate pathway
glycogen synthesis and catabolism
gluconeogenesis

53. Section 2
Glycolysis

54. Glycolysis
The anaerobic catabolic pathway by which a molecule of glucose is broken down into two molecules of lactate.
glucose →2lactic acid (lack of O2)
All of the enzymes of glycolysis locate in cytosol.

55. 1、The Development of Biochemistry and the Delineation of Glycolysis Went Hand by Hand
1897, Eduard Buchner (Germany), accidental observation : sucrose (as a preservative) was rapidly fermented into alcohol by cell-free yeast extract.
The accepted view that fermentation is inextricably tied to living cells (i.e., the vitalistic dogma) was shaken and Biochemistry was born: Metabolism became chemistry!
1900s, Arthur Harden and William Young Pi is needed for yeast juice to ferment glucose, a hexose diphosphate (fructose 1,6-bisphosphate) was isolated.

56. 1900s, Arthur Harden and William Young (Great Britain) separated the yeast juice into two fractions: one heat-labile, nondialyzable zymase (enzymes) and the other heat-stable, dialyzable cozymase (metal ions, ATP, ADP, NAD+).
1910s-1930s, Gustav Embden and Otto Meyerhof (Germany), studied muscle and its extracts:
Reconstructed all the transformation steps from glycogen to lactic acid in vitro; revealed that many reactions of lactic acid (muscle) and alcohol (yeast) fermentations were the same!
Discovered that lactic acid is reconverted to carbohydrate in the presence of O2 (gluconeogenesis); observed that some phosphorylated compounds are energy-rich.

57. (Glycolysis was also known as Embden-Meyerhof pathway).
The whole pathway of glycolysis (Glucose to pyruvate) was elucidated by the 1940s.

58. 2、The overall glycolytic pathway can be divided into two phases
The hexose is first phophorylated (thus activated) and then cleaved to produce two three-carbon intermediates at the preparatory phase, consuming ATP.
The three-carbon intermediates are then oxidized during the payoff phase, generating ATP and NADH.
All intermediates are phosphorylated (as esters or anhydrides) with six (derivatives of Glucose or Fructose) or three carbons (derivatives of dihydroxyacetone, glyceraldehyde, glycerate, or pyruvate).

59. Ten steps of reactions are involved in the pathway.
Only a small fraction (~5%) of the potential energy of the glucose molecule is released and much still remain in the final product of glycolysis, pyruvate.
All the enzymes are found in the cytosol (pyruvate will enter mitochondria for further oxidation).

60. 3. The procedure of glycolysis
glycolytic pathway
pyruvate
lactic acid

61. 1) Glycolytic pathway :
G → pyruvate
including 10 reactions.

62. (1) G phosphorylated into glucose 6-phosphate
Phosphorylated G cannot get out of cell
Hexokinase , HK (4 isoenzymes) ,
glucokinase, GK in liver ;
Irreversible ；
The reaction is exergonic.

63. The first reaction - phosphorylation of glucose
Hexokinase or glucokinase
This is a priming reaction - ATP is consumed here in order to get more later
ATP makes the phosphorylation of glucose spontaneous

64. Comparison of hexokinase and glucokinase
hexokinase glucokinase
occurrence in all tissues only in liver
Km value mmol/L mmol/L
Substrate G, fructose, glucose
mannose
Regulation G-6-P Insulin
Comparison of hexokinase and glucokinase

66. (2) G-6-P → fructose 6-phosphate
可逆的反应
Phosphohexose isomerase (also called phosphoglucose isomerase) catalyzes the isomerization from glucose 6-P to fructose 6-P, converting an aldose to a ketose.

67. (3) F-6-P → fructose 1,6-bisphosphate
The second phosphorylation
Phosphofructokinase-1 (PFK-1, 磷酸果糖激酶-1) then catalyzes the second phosphorylation step, converting fructose 6-P to fructose 1,6-bisphosphate; the overall rate of glycolysis is mainly controlled at this step; PFK-1 is a highly regulatory enzyme.
酶的活性相对较低

68. (4) F-1,6-BP → 2 Triose phosphates
Aldolase (醛缩酶), named for the reverse reaction catalyzes the cleavage (“lysis”) of fructose 1,6-bisphosphate from the middle C-C bond to form two 3-carbon sugars, dihydroxyacetone phosphate and glyceraldehyde 3-phosphate; this is a reversal aldol condensation reaction.

70. (5) Triose phosphate isomerization
A hydrogen atom is transferred from C-1 to C-3.
G→2 molecule glyceraldehyde-3-phosphate, consume 2 ATP .

71. (6) Glyceraldehyde 3-phosphate → glycerate 1,3-bisphosphate
Glyceraldehyde 3-phosphate dehydrogenase catalyzes first the oxidation and then the phosphorylation of glyceraldehyde 3-P to form glycerate 1,3-bisphosphate, an acyl phosphate (酰基磷酸); 2e- are collected by NAD+; a thioester (硫酯) intermediate is formed between glyceraldehyde 3-P and an essential Cys residue of the enzyme; Pi is used here for the phosphorolysis (磷酸解作用); the phosphate group linked to the carboxyl group via a anhydride bond has a high transfer potential.
高能磷酸键

72. (7) 1,3-BPG → glycerate 3-phosphate
产生ATP
The phosphoglycerate kinase catalyzes the direct transfer of the anhydride phosphate in 1,3-BPG to an ADP to generate an ATP; this is called the substrate-level phosphorylation; 1,3-BPG is a high energy intermediate that leads to ATP formation.

73. Substrate-Level Phosphorylation
ATP is formed when an enzyme transfers a phosphate group from a substrate to ADP.
Enzyme
Substrate O-
C=O
C-O-
CH2 P
Adenosine
ADP
(PEP)
Example:
PEP to PYR P
ATP O-
C=O
CH2
Product
(Pyruvate)
Adenosine

74. (8) Glycerate 3-phosphate → glycerate 2-phosphate
The phosphoglycerate mutase变位酶 catalyzes the shift of phosphoryl group on 3-phosphoglycerate from C-3 to C-2.

75. 2,3-bisphosphoglycerate is both a coenzyme for the mutase and an intermediate for the reaction; a His residue on the mutase takes phosphoryl group from C-3 of 2,3-BPG and adds it to C-2 of 3-phosphoglycerate, thus forming a phosphorylation cycle; this mutase act in a very similar way as phosphoglucomutase.

76. (9) Glycerate 2-phosphate → phosphoenol pyruvate
Enolase (烯醇酶) catalyzes the elimination of a H2O from 2-phosphoglycerate to generate phosphoenolglycerate (PEP) with the transfer potential of the phosphoryl group dramatically increased.
磷酸烯醇式丙酮酸

77. (10) PEP →pyruvate Second substrate level phosphorylation Irreversible
The pyruvate kinase catalyzes the transfer of the phosphoryl group on PEP to ADP to form another molecule of ATP by “substrate-level phosphorylation”; enolpyruvate is formed and is quickly tautomerized to pyruvate (丙酮酸).

78. PEP to Pyruvate makes ATP
These two ATP (from one glucose) can be viewed as the "payoff" of glycolysis
Large, negative G - regulation!
This is the third irreversible reaction specific
for glycolysis★

80. Lactate dehydrogenase
2) Pyruvate → lactate
Under anaerobic conditions
Lactate dehydrogenase
(LDH)
NADH + H+
NAD+
Pyruvate
Lactate
NADH+H+ come from the 6th step of glycolysis (glyceraldehyde-3-phosphate dehydrogenase reaction) .
The process from glucose to lactate under anaerobic condition is referred to as anaerobic glycolysis. ★

81. Overview of Glycolysis★
It is basically an anaerobic process
Cellular location: cytosol
Ten reactions - same in all cells - but rates differ
Two phases:
A series of reactions in 1st: glucose is broken down to two moleculars of glyceraldehyde-3-phosphate
2nd produces two pyruvates, ATPs and NADH
Three possible fates for pyruvate

83. Glyceraldehyde-3-phosphate
The first phase
Dihydroxyacetone
phosphate
Glucose +
Glyceraldehyde-3-phosphate

84. Glycolysis A. Energy Investment Phase: C-C-C-C-C-C C-C-C Glucose (6C)
Glyceraldehyde phosphate (2 - 3C)
(G3P or GAP)
2 ATP used
0 ATP produced
0 NADH - produced
2ATP
2ADP + P
,ɡlisə’rældihaid] 甘油醛

85. The preparatory Phase of glycolysis
Group
transfer
Isomerization
Group
transfer
Aldol
cleavage
Isomerization

86. Glycolysis B. Energy Yielding Phase Glyceraldehyde phosphate (2 - 3C)
(G3P or GAP)
Pyruvate (2 - 3C)
(PYR)
0 ATP used
4 ATP produced
2 NADH - produced
4ATP
4ADP + P
C-C-C C-C-C
GAP
(PYR)
[pai‘ru:veit]

87. The payoff phase of glycolysis
Dehydrogenation
Group
transfer
Group shift
Dehydration
Group
transfer

88. Summary of Glycolysis

89. Total reaction: Formation of ATP:
C6H12O6 + 2ADP + 2Pi CH3CHOHCOOH + 2ATP + 2H2O
Formation of ATP:
The net yield is 2 ~P or 2 molecules of ATP per glucose.

90. Question
Which of the following enzymes catalyzes a substrate-level phosphorylation reaction?
A hexokinase
B pyruvate kinase
C glyceraldehyde-3-phosphate dehydrogenase
D phosphoglycerate kinase
E B and D
The substrate level phosphorylation occurs in the process of ?

91. 4. Regulation of Glycolysis
Three key enzymes catalyze irreversible reactions : Hexokinase, Phosphofructokinase & Pyruvate Kinase.

92. 1) PFK-1
The reaction catalyzed by PFK-1 is usually the rate-limiting step of the Glycolysis pathway.
This enzyme is regulated by covalent modification, allosteric regulation.

93. Regulation of PFK-1
ATP is a substrate and an allosteric inhibitor of PFK-1
AMP allosterically activates PFK-1 by relieving the ATP inhibition (ADP is also an activator in mammalian systems)
Changes in AMP and ADP concentrations can control the flux through PFK-1
Elevated levels of citrate (indicate ample substrates for citric acid cycle) also inhibit PFK-1
ATP抑制，负反馈调节；

94. Regulation of PFK-1 by Fructose 2,6-bisphosphate (F2,6BP)
F2,6-BP is a potent activator of PFK-1
F2,6-BP is formed from F6P by phosphofructokinase-2 (PFK-2), which is a bi-functional enzyme
b-D-Fructose 2,6-bisphosphate
Formation and hydrolysis of F2,6-BP

95. bifunctional enzyme
Glucagon胰高血糖素

96. 2) Pyruvate kinase Allosteric regulation:
F-1,6-BP acts as allosteric activator；
ATP and Ala in liver act as allosteric inhibitors;

97. Covalent modification:
phosphorylated by Glucagon through cAMP and PKA and inhibited.

98. Regulation of Pyruvate Kinase
Four PK isozymes exist in mammalian tissues
PK is allosterically activated by F1,6BP, inhibited by ATP
Glucagon stimulates protein kinase A which phosphorylates PK converting it to a less active form (liver and intestinal cells)
胰高血糖素
Activator F1,6BP (red) bound with PK

99. 3) Hexokinase and glucokinase
This enzyme is regulated by covalent modification, allosteric regulation and isoenzyme regulation.
Inhibited by its product G-6-P.
Insulin induces synthesis of glucokinase.

100. Regulation of glycolysis
1. When ATP levels are sufficient, glycolysis activity decreases
Hexokinase inhibited by excess glucose 6-phosphate
PFK-1 is inhibited by ATP and citrate
Pyruvate kinase is inhibited by ATP
2. When ATP is needed, glycolysis is activated
AMP (the product of ATP consumption) relieve the inhibition of PFK-1 by ATP
Fructose 2,6-bisphosphate (F2,6BP) relieve the inhibition of PFK-1 by ATP
Pyruvate kinase is activated by F1,6BP
Step 1
Step 3
Step 10

101. Question
In an erythrocyte undergoing glycolysis, what would be the effect of a sudden increase in the concentration of
A. ATP? B. AMP?
C. fructose-1,6-biophosphate?
D. fructose-2,6-biophosphate?
E. citrate? F. glucose-6-phosphate?

102. Answer Increased [ATP] or [citrate] inhibits glycolysis.
Increased [AMP][fructose-1,6-biophosphate][fructose-2,6-biophosphate],or[glucose-6-phosphate]stimulate glycolysis

103. The Fate of NADH NADH is energy - two possible fates:
If O2 is available, NADH enters into Mitochondria by two ways, where it is re-oxidized in the electron transport pathway, making ATP in oxidative phosphorylation.
In anaerobic conditions, NADH is re-oxidized by lactate dehydrogenase (LDH), providing additional NAD+ for more glycolysis

104. Other Substrates for Glycolysis
Glycerol, Fructose, mannose and galactose
Glycerol is changed into DHAP
Fructose is primed and cleaved to form dihydroxyacetone phosphate and glyceraldehyde, which are further converted to glyceraldehyde 3-P.
Galactose is first converted to Glc-1-P via a UDP-galactose intermediate and UDP-glucose intermediate, then to Glc-6-P.
甘露糖，半乳糖

105. One fructose is converted to two glyceraldehyde 3-P
Triose phosphate
isomerase

106. Galactose is converted to glucose 6-P via a UDP-galactose intermediate
Glc-P-P-Uridine
Galactose is converted to
glucose 6-P via a
UDP-galactose intermediate

109. Significance of Glycolysis
Glycolysis is the emergency energy-yielding pathway. Produce ATPs
Glycolysis is the main way to produce ATP in some tissues, even though the oxygen supply is sufficient, such as red blood cells, retina, testis, skin, medulla of kidney.
In glycolysis, 1mol G produces 2mol lactic acid and 2mol ATP.

111. The importance of anaerobic glycolysis
Only 2ATP(14.6kcal) formed in anaerobic [,ænεə'rəubik] glycolysis, whereas the complete oxidation of glucose produces 270kcal
However, anaerobic glycolysis is usefull ★
Mature erythrocyte need anaerobic glycolysis produce energy (RBC doesn’t have mitochondria)
When human doing strenuous剧烈的 exercise (ie sprint), skeletal muscle use ATP from anaerobic glycolysis
Ischemic缺血性的 tissues, nerve etc, use anaerobic glycolysis

112. Summary
D-glucose is a commonly used as fuel and versatile precursor in almost all organisms.
The study of glucose degradation has a rich history in biochemistry (especially for enzymology).
Glucose is first converted into two three-carbon pyruvates via the ten-step glycolysis pathway without directly consuming O2 and with a net production of two ATP molecules by substrate-level phosphorylation.
Limited amount of energy can be released by oxidizing glucose under anaerobic conditions by fermentation.

113. The enzymes participating glycolysis may form multiple enzyme complexes, where substrate is channeled from one enzyme to another.
The sugar units on glycogen is converted to glucose 1-phosphate via phosphorolysis, which is catalyzed by glycogen phosphorylase.
Other monosaccharides are also converted to intermediates of glycolysis for further oxidative degradation.

114. Phosphofructokinase-1 (PFK-1) is the main point of regulation for controlling the rate of glycolysis.
The activity of PFK-1 is regulated by various effectors having various signaling messages of the cell metabolism.
Glycolysis and gluconeogenesis is reciprocally regulated to avoid “futile cycling” of synthesis and degradation.

115. Mutiple choice Glycolysis （ ） A. takes place in the mitochondrion.
B. is the major provider of ATP to muscle during heavy exercise.
C. is controlled by levels of fructose-2,6 bis phosphate.
D. is the only pathway known from glucose to pyruvate.
E. is anaerobic pathway.

116. Aerobic Oxidation of Glucose
Section 3
Aerobic Oxidation of Glucose
需氧氧化

117. Fates of Pyruvate Potential energy = 2840 kJ/mol Go’= -146 kJ/mol
Ethanol fermentation (occurring in yeast and other microorganisms): pyruvate is first decarboxylated and then reduced by NADH, catalyzed by pyruvate decarboxylase and alcohol dehydrogenase respectively.
Go’= -146 kJ/mol
乙醇发酵
Go’= kJ/mol
Go’= -196 kJ/mol
Go’= -235 kJ/mol

118. The process of complete oxidation of glucose to CO2 and water with liberation of energy as the form of ATP is named aerobic oxidation.
The main pathway of G oxidation.

119. Under aerobic conditions
Under aerobic condition, the process which glucose is completely oxidized to CO2 and H2O is called aerobic oxidation
The process take in cytosol and mitochondrion
Aerobic oxidation:
The first stage----glycolysis, pyruvate is produced
The second stage----pyruvate is oxidized to acetyl-CoA
The third stage---TCA cycle and oxidative phosphorylation
乙酰辅酶A

120. 1. Process of aerobic oxidationy t o s o l M i t o c h o d r i a f i r s t s e c o n d t h i r d s t a g e s t a g e s t a g e G P y r P y r C H C O ~ S C o A C O + H O + A T P 3 2 2 g l y c o l y t i c T C A p a t h w a y

121. 1) Oxidative decarboxylation of Pyruvate to Acetyl CoA
irreversible;
in mitochodria.

122. Pyruvate dehydrogenase complex:
E1 pyruvate dehydrogenase
Es E2 dihydrolipoyl transacetylase
E3 dihydrolipoyl dehydrogenase
thiamine pyrophosphate, TPP (VB1)
HSCoA (pantothenic acid)
cofactors lipoic Acid
NAD+ (Vpp)
FAD (VB2)

123. Pyruvate dehydrogenase complex:
HSCoA
NAD+

124. pyruvate dehydrogenase complex
The structure of
pyruvate dehydrogenase complex

126. HSCoA

127. Arsenic(砷) Compounds Are Poisonous in part
because They Sequester Lipoamide（硫辛酰胺）

128. 1. -羟乙基-TPP的生成
CO2
2.乙酰硫辛酰胺的生成
NADH+H+
5. NADH+H+的生成
NAD+
CoASH
3.乙酰CoA的生成
4. 硫辛酰胺的生成

130. Question
Which is Not the coenzyme of the Pyruvate Dehydrogenase Complex（ B ）
A. NAD B. FMN
C. FAD D. TPP
E. COA-SH

131. 2) Tricarboxylic acid cycle, TCAC
The cycle comprises the combination of a molecule of acetyl-CoA with oxaloacetate, resulting in the formation of a six-carbon tricarboxylic acid, citrate. There follows a series of reactions in the course of which two molecules of CO2 are released and oxaloacetate is regenerated.
Also called citrate cycle or Krebs cycle.

132. The TCA Cycle ★
Tricarboxylic acid cyle (TCA cycle), is also called Citric Acid Cycle or Krebs Cycle
A common metabolic pathway for glucose, amino acid and fatty acid
Pyruvate from glycolysis is degraded to CO2
Some ATP is produced
More NADH is made
NADH goes on to make more ATP in electron transport and oxidative phosphorylation

135. (1) Process of reactions
Step 1 The methyl carbon of acety-CoA joins the carbonyl carbon of oxaloacetate via aldol condensation to form citrate (柠檬酸).

136. Citryl-CoA is a transiently intermediate but hydrolyzed immediately in the active site of citrate synthase; hydrolysis of the thioester bond releases a large amount of free energy, driving the reaction forward; large conformational changes occur after oxaloacetate is bound and after citryl-CoA is formed, preventing the undesirable hydrolysis of acetyl-CoA.

137. Step 2:Citrate is isomerized into isocitrate (get the six-carbon unit ready for oxidative decarboxylation) via a dehydration step followed by a hydration step; cis-aconitate (顺乌头酸) is an intermediate during this transformation, thus the catalytic enzyme is named as aconitase, which contains a 4Fe-4S iron-sulfur center directly participating substrate binding and catalysis.

138. Step 3: Isocitrate is first oxidized and then decarboxylated to form a-ketoglutarate (a-酮戊二酸); oxalosuccinate is an intermediate; two electrons are collected by NAD+; the carbon released as CO2 is not from the acetyl group joined; catalyzed by isocitrate dehydrogenase.

139. Isocitrate Dehydrogenase, IDH
Oxidative decarboxylation of isocitrate to yield  -ketoglutarate
Classic NAD+ chemistry (hydride removal) followed by a decarboxylation
Isocitrate dehydrogenase is a link to the electron transport pathway because it makes NADH
Know the mechanism!
异柠檬酸脱氢酶

141. Step 4 a-ketoglutarate undergoes another round of oxidative decarboxylation; decarboxylated first, then oxidized to form succinyl-CoA (琥珀酰辅酶A); again the carbon released as CO2 is not from the acetyl group joined; catalyzed by a-ketoglutarate dehydrogenase complex; reactions and enzymes closely resemble pyruvate dehydrogenase complex (with similar E1 and E2, identical E3).

142.  -Ketoglutarate Dehydrogenase Complex
A second oxidative decarboxylation
This enzyme is nearly identical to pyruvate dehydrogenase - structurally and mechanistically
Five coenzymes used - TPP, CoASH, Lipoic acid, NAD+, FAD
You know the mechanism if you remember pyruvate dehydrogenase
Another target for arsenic compounds

143. Step 5 Succinyl-CoA is hydrolyzed to succinate (琥珀酸或戊二酸); the free energy released by hydrolyzing the thioester bond is harvested by a GDP or an ADP to form a GTP or an ATP by substrate-level phosphorylation;

144. The reversible reaction is catalyzed by succinyl-CoA synthetase (or succinic thiokinase); acyl phosphate and phosphohistidyl enzyme are intermediates; the active site is located at the interface of two subunits; the negative charge of the phospho-His intermediate is stabilized by the electric dipoles of two a helices (one from each subunit).

145. Succinyl-CoA Synthetase
A substrate-level phosphorylation
A nucleoside triphosphateGTP is made
Its synthesis is driven by hydrolysis of a CoA ester
The mechanism involves a phosphohistidine

147. Step 6 Succinate is oxidized to fumarate (延胡索酸或反丁烯二酸); catalyzed by a flavoprotein succinate dehydrogenase (with a covalently bound FAD and three iron-sulfur centers), which is tightly bound to the inner membrane of mitochondria; malonate (丙二酸) is a strong competitive inhibitor of the enzyme, that will block the whole cycle.
其他的酶都是在线粒体基质中

148. Succinate Dehydrogenase
An oxidation involving FAD
This enzyme is actually part of the electron transport pathway in the inner mitochondrial membrane
The electrons transferred from succinate to FAD (to form FADH2) are passed directly to ubiquinone (UQ) in the electron transport pathway

149. Step 7 Fumarate is hydrated to L-malate by the action of fumarase; the enzyme is highly stereospecific, only act on the trans and L isomers, not on the cis and D isomers (maleate and D-malate);

150. Step 8 Oxaloacetate is regenerated by the oxidation of L-malate; this reaction is catalyzed by malate dehydrogenase with two electrons collected by NAD+.

151. Citrate cycle

152. Summary of Krebs Cycle ①
Reducing equivalents

153. ② The net reaction of the TCAC:
acetylCoA+3NAD++FAD+GDP+Pi+2H2O
→ 2CO2+3NADH+3H++FADH2+GTP+ HSCoA
③ Irreversible and aerobic reaction
④ The enzymes are located in the mitochondrial matrix.

154. ⑤ Anaplerotic reaction of oxaloacetate
补给反应

156. ⑥The Fate of Carbon in TCA
Each cycle, 2 carbon become CO2
It’s nearly, 1 acetyl-CoA was oxidized during 1 cycle
If lable acetyl-CoA using 14C, you will find carbon of CO2 is from oxaloacetate, not acetyl-CoA
Maybe during the cycle, they change C with each other
Intermediate products of the cycle including oxaloacetate are not change. They come from glucose

157. (2) Bio-significance of TCAC
① Acts as the final common pathway for the oxidation of carbohydrates, lipids, and proteins.
② Serves as the crossroad for the interconversion among carbohydrates, lipids, and non-essential amino acids, and as a source of biosynthetic intermediates.

158. Krebs Cycle is at the hinge of metabolism.

159. 2. ATP produced in the aerobic oxidation

160. acetyl CoA → TCAC : 3 (NADH+H+) + FADH2 + 1GTP → 10 ATP.
pyruvate →acetyl CoA: NADH+H+ → 2.5 ATP
1 G → 2 pyruvate : 2(NADH+H+) → 5 or 7ATP
1mol G： 30 or 32mol ATP
（10＋2.5 ）×2 ＋ 5（ 7 ）＝30（ 32 ）

161. 3. The regulation of aerobic oxidation
The Key Enzymes of aerobic oxidation
The Key Enzymes of glycolysis
Pyruvate Dehydrogenase Complex
Citrate synthase
Isocitrate dehydrogenase (rate-limiting )
-Ketoglutarate dehydrogenase

162. (1) Pyruvate dehydrogenase complex
FA:fatty acid脂肪酸

163. (3) Isocitrate dehydrogenase
(2) Citrate synthase
Allosteric activator: ADP
Allosteric inhibitor: NADH, succinyl CoA, citrate, ATP
(3) Isocitrate dehydrogenase
Allosteric activator: ADP, Ca2+
Allosteric inhibitor: ATP
(4) -Ketoglutarate dehydrogenase
Similar with Pyruvate dehydrogenase complex

165. Regulation of the TCA cycle

166. Oxidative phosphorylation→TCAC↑
ATP/ADP↑ inhibit TCAC,
Oxidative phosphorylation ↓
ATP/ADP↓，promote TCAC，
Oxidative phosphorylation ↑

167. 4. Pasteur Effect The key point is NADH ： NADH mitochondria
Under aerobic conditions, glycolysis is inhibited and this inhibitory effect of oxygen on glycolysis is known as Pasteur effect.
The key point is NADH ：
NADH mitochondria
Pyr TCAC CO2＋H2O
Pyr can’t produce to lactate.

168. The Pasteur Effect
Under anaerobic conditions the conversion of glucose to pyruvate is much higher than under aerobic conditions (yeast cells produce more ethanol and muscle cells accumulate lactate)
The Pasteur Effect is the slowing of glycolysis in the presence of oxygen
More ATP is produced under aerobic conditions than under anaerobic conditions, therefore less glucose is consumed aerobically

169. Pentose Phosphate Pathway
Section 4
Pentose Phosphate Pathway

170. Pentose Phosphate Pathway
Aka:
Pentose shunt
Hexose monophosphate shunt
Phosphogluconate pathway
It occurs in the cytosol ★.
Two oxidative processes followed by five non-oxidative steps
Operates active in the cytosol of liver and adipose cells

171. Pentose Phosphate Pathway ★
Pentose phosphate pathway converts glucose to specialized products needed by the cells
Provides NADPH
Produces ribose-5-P 25
171

172. Glucose 30% Glycogen Glucose-6-P PPP 70% Fructose-6-P Glycolysis
PPP :Pantose phosphate pathway
Fructose-6-P
Glycolysis
172

174. 1.Oxidative Phase Glucose-6-P Dehydrogenase Gluconolactonase 葡糖酸内酯酶
Irreversible 1st step - highly regulated (inhibited by NADPH)
Gluconolactonase 葡糖酸内酯酶
Uncatalyzed reaction happens too
6-Phosphogluconate Dehydrogenase
An oxidative decarboxylation 26
174

175. Regulatory enzyme
6-磷酸葡萄糖酸内酯
The enzyme is highly specific for NADP+; the Km for NAD+ is 1000 greater than for NADP+.
175

178. Oxidative Phase

179. 2. The Nonoxidative Phase
Transketolase转酮醇酶
transfer of two-carbon units
Transaldolase 转酰酶
transfers a three-carbon unit 27
179

180. + + + 5 5 3 7 6 4 + + 4 5 6 3
C5 + C5 --> C7 + C3
C7 + C3 --> C4 + C6
C5 + C4 --> C6 + C3
Sum:
3C5 --> 2C6 + C3
180

181. 差向异构酶
181

182. 182

184. 184

185. Non-Oxidative Phase Transketolase: requires TPP Transaldolase
Ribose 5-p
Xylulose 5-p
Fructose 6-p
Glyceraldehyde 3-p
Glycolysis
Transketolase: requires TPP
Transaldolase

186. 3×Glucose 6-phosphate+ 6 NADP+ +glyceradehyde-3-phosphate
The total reactions ★
3×Glucose 6-phosphate+ 6 NADP+
2×Frucose 6-phosphate
+glyceradehyde-3-phosphate
+6NADPH+H++3CO2

187. 3. Regulation of pentose phosphate pathway
Glucose-6-phosphate Dehydrogenase is the rate-limiting enzyme.
NADPH/NADP+↑, inhibit;
NADPH/NADP+↓, activate.

188. 4. Significance of pentose Phosphate pathway
1) To supply ribose 5-phosphate for bio-synthesis of nucleic acid;
2) To supply NADPH as H-donor in metabolism;
NADPH is very important “reducing power” for the synthesis of fatty acids and cholesterol, and amino acids, etc.

189. NADPH is the coenzyme of glutathione reductase谷胱甘肽还原酶 to keep the normal level of reduced glutathione;
So, NADPH, glutathione and glutathione reductase together will preserved the integrity of RBC membrane.

190. Deficiency缺乏 of glucose 6-phosphate dehydrogenase results in hemolytic anemia溶血性贫血 (favism).
NADPH serves as the coenzyme of mixed function oxidases (mono-oxygenases). In liver this enzyme participates in biotransformation.

192. Variations on the Pentose Phosphate Pathway
1) More ribose-5-P than NADPH is needed
2) Both ribose-5-P and NADPH are needed
3) More NADPH than ribose-5-P is needed
4) NADPH and ATP are needed, but ribose-5-P is not 28
192

193. Rapidly dividing cells require more ribose 5- phosphate than NADPH.
集中在第二个阶段 nonoxidative phase

194. The need for NADPH and ribose 5-phosphate is balanced.
不用进入第二阶段转化

195. More NADPH is needed than ribose 5-phosphate; Fatty acid synthesis in adipose cells.

196. The cell needs both NADPH and ATP

197. Question
What are the most important products that cells generate by means of the pentose phosphate pathway? ( )
A. lactate and ATP.
B. ribose-5-phosphate and NADPH.
C. NADP+ and ribose-5-phosphate.
D. NADPH and UDP-ribose.
E. ribulose-1,5-bisphosphate and NADPH.

198. Section 5
Glycogen Metabolism

199. Glycogen Breakdown Glycogen Synthesis Glycogen Storage Diseases
Glycogen Metabolism
Glycogen Breakdown
Glycogen Synthesis
Glycogen Storage Diseases
199
199

200.  (1→4) glycosidic bonds, mainly
Glycogen is a polymer of glucose residues linked by
 (1→4) glycosidic bonds, mainly
 (1→6) glycosidic bonds, at branch points.

201. 201
201

202. Glycogen Glycogen serves as storage carbohydrate in animals, insects
and fungi
Heavily branched to allow rapid
mobilization of glycogen

203. Glycogen Breakdown
Glycogen in cells is first converted to Glc-6-P for oxidative degradation氧化降解
Glycogen Storage Diseases
203
203

204. Glycogen in cells is first converted to Glc-6-P for oxidative degradation★
Glycogen Breakdown Requires Three Enzymes
A. Glycogen phosphorylase to cleave a1,4 linkages
Glycogen + Pi > Glycogen + Glc-1-P
n residues n-1 residues
B. Glycogen debranching enzyme脱支酶
a(1-4) glycosyl transferase and a(1-6) glucosidase activities -> Glc-1-P and Glc
C. Phosphoglucomutase to convert to usable form
Glc-1-P > Glc-6-P
Glc-6-phosphatase is required for export from liver as Glc
204

205. No escape
No ATP
Consumed!
The glucose unit at the nonreducing terminal of glycogen is removed as Glc-1-P via phosphorolysis: The (a1- 4) glycosidic bond is attacked by an inorganic phosphate). Catalyzed by glycogen phosphorylase (a tetramer).

206. Glycogen Phosphorylase
Tetrameric
glycogen
phosphorylase
(the b form)
206

207. glycogen phosphorylase’s coenzyme pyridoxal phosphate (PLP, 磷酸吡哆醛) derived from vitamin B6) act as a general acid-base catalyst.

208. PLP acts as a general acid-base in the active site of glycogen phosphorylase

209. Glycogen phosphorylase reaction mechanism
1. Formation of an EPiglycogen ternary complex.
2. Oxonium ion intermediate (I) formation from the -linked terminal glucosyl residue involving acid catalysis by Pi facilitated by proton transfer from PLP.
3. Reaction of Pi with overall retention of configuration around C1 to form -D-Glc-1-phosphate. The glycogen, minus one residue, cycles back to step 1.
209

210. Glycogen Debranching Enzyme
Two active sites for two different catalytic activities-a bifunctional enzyme
Required for degradation of almost half of glycogen molecule
Maximal rate of debranching enzyme much slower than that of glycogen phosphorylase

211. Glycogen Debranching Enzyme
Nonreducing ends
(1→6) linkage
Glycogen phosphorylase
(1→6) glucosidase activity of debranching enzyme
Glucose
Transferase activity of debranching enzyme
Acts as an (14)
transglycosylase
(glycosyl transferase)
by transferring an
(14) linked
trisaccharide unit from a “limit branch” of glycogen to the
nonreducing end of
another branch.
Also catalyzes the hydrolysis of the (16) bond
of the remaining
glycosyl residue to
yield Glc.
Glucose-1-phosphate
211

212. Phosphoglucomutase
Mechanism of action is similar to that of phosphoglycerate mutase except Ser carries phosphoryl group here.
The phosphglucomutase shifts the phosphoryl group from position C-1 to position C-6 on the glucose unit.
212

213. Summary:
Glycogen catabolism (glycogenolysis)
Phosphorylase: key E;
The end products: 85% of G-1-P and 15% of free G;
There is no the activity of glucose 6-phosphatase (G-6-Pase) in skeletal muscle but in liver.

214. Glycogen synthesis (Glycogenesis)
The process of glycogenesis occurs in cytosol of liver and skeletal muscle mainly.

215. Glycogen
degradation
Glycogen
synthesis
Glycogen synthesis initially was thought to occur through a direct reverse of the degradation reaction wrong

216. Leloir discovered in 1949 that one hexose is transformed to another via sugar nucleotide and in 1959 that glycogen is synthesized from UDP-glucose!
Sugar nucleotides were found to be the activated forms of sugars participating in biosynthesis of glucose.

217. Glycogen Synthesis ★ Glucose must be activated into UDP-Glc
Notice: ADP-Glc for Starch; GDP-Glc or UDP-Glc for Cellulose (纤维素)
The primer is required
Glycogenin糖原素
Proceed from the reducing end to the non-reducing end
Glycogen synthase and Glycogen branching enzyme

218. UDP-Glc Synthesis UDP-Glucose Pyrophosphorylase
converts UTP and Glc-1-P to UDP-Glc and pyrophosphate.
Inorganic pyrophosphatase converts PPi to 2Pi, driving reaction

219. Use of UDP-Glc makes synthesis reaction favorable
UDPG’s “high-energy” status permits it to donate glucosyl units to the growing glycogen chain in a thermodynamically favorable reaction.
This is a common strategy for carbohydrate addition.
219

220. The overall reaction for the formation of UDPG is highly exergonic.

221. Glycogen synthase ★
Glycogen is added in a 1,4 linkage from UDP-Glc to the non-reducing end of a glycogen chain
The reaction mechanism is apparently like that of phosphorylase

222. Glycogen is extended from the
nonreducing end using UDP-glucose

223. Glycogenin ★
Glycogen synthase can only extend a chain- cannot initiate de novo synthesis从头合成
How is glycogen synthesis initiated?
The first step is attachment of a Glc residue to Tyr194 -OH group of the glycogenin protein by a tyrosine glucosyltransferase.
Glycogenin autocatalytically extends the glucan chain by up to 7 additional UDP-Glc-supplied residues, forming a primer for the initiation of glycogen synthesis.
Once primer started, glycogen synthase can associate to form ternary complex三元络合物; upon extension of the chain, glycogenin dissociates from the complex

226. Glycogen branching by amylo-(1,41,6)-transglycosylase.
Transfer of terminal
chain segments of
about 7 glucosyl
residues to the C6-OH
groups of Glc
residues on the same
or another glycogen
chain.
Each segment must
come from a chain
of at least 11 residues
and the new branch
point must be at least
4 residues away from
other branch points. This reflects the structure of the catalytic site.
Donor from a branch at
least 11 residues long
New branch at least 4 residues from another branch
226

227. Summary:Glycogen synthesis

228. Glycogen Storage Diseases Affect Primarily Liver and/or Muscle
Liver symptoms, most often manifested in infancy or childhood:
Hepatomegaly肝肿大 (accumulation of normal or abnormal glycogen and sometimes fat),
Hypoglycemia (lack of glycogen degradation)
Muscle symptoms more often manifest later in life as muscle mass increases, and are most often weakness, pain and myolysis肌溶解 upon strenuous exercise剧烈运动, and myopathy肌病

229. Glycogen synthase and glycogen phosphorylase are reciprocally相互地 regulated in vertebrates by hormones
Phosphorylation and dephosphorylation have opposite effects towards the enzymatic acitivities of these two enzymes.
Hormones like epinephrine (acting on muscle cells) or glucagon (acting on liver cells) will activate protein kinase A, which will lead to phosphorylation modification of both the glycogen phosphorylase (thus activating it) and the glycogen synthase (thus inactivating it).

230. Glycogen synthase and phosphorylase
are reciprocally
regulated by
hormones via
phosphorylation-
dephosphorylation

232. Section 6
Gluconeogenesis糖异生

233. ['ɡlu:kəu,ni:əu'dʒenisis]
Gluconeogenesis★
['ɡlu:kəu,ni:əu'dʒenisis]
The synthesis of the glucose or glycogen from non-carbohydrate sources, namely the amino acids, lactate, propionate, and glycerol. . 3

234. Concept:
The process of transformation of non-carbohydrates to glucose or glycogen is termed as gluconeogenesis.
Materials: lactate, glycerol甘油，丙三醇, pyruvate and glucogenic amino acid糖原性氨基酸.
Most fatty acids yield产生 only acetyl-CoA ;Acetyl-CoA (through TCA cycle) cannot provide for net synthesis of sugars )
Site: mainly liver, kidney.

235. 1. Gluconeogenic pathway
The main pathway for gluconeogenesis is essentially a reversal of glycolysis, but there are three energy barriers obstructing阻塞 a simple reversal of glycolysis.

236. 1) The shunt of carboxylation of Pyr

238. Linkage of biotin to lysine residue in pyruvate carboxylase

240. Membrane barrier and energy barrier

241. Summarization pyruvate OAA PEP
ATP
ADP+Pi
CO2 ①
GTP
GDP
CO2 ②
pyruvate
OAA
PEP
① pyruvate carboxylase (丙酮酸羧化酶)，coenzyme is biotin, mitochondria
② phosphoenolpyruvate carboxykinase(磷酸烯醇式丙酮酸羧激酶), mitochondria and cytosol

242. gluconeogenesis
转氨基
OAA—malate----cross the membrane ;OAA---Asp

243. 2) F-1, 6-BP →F-6-P

244. 3) G-6-P →G

245. Glucose-6-Phosphatase
Conversion of Glucose-6-P to Glucose
Presence of G-6-Pase in endoplasmic reticulum of liver and kidney cells makes gluconeogenesis possible
Muscle and brain do not do gluconeogenesis
G-6-P is hydrolyzed as it passes into the ER 10

246. Glucose-6-phosphatase is localized in the ER

247. 2 lactic acid → G consume ATP?

248. From pyruvate
to PEP: two
alternative paths

249. gluconeogenesis

250. Summary: Gluconeogenesis
Something Borrowed, Something New
Seven steps of glycolysis are retained:
Steps 2 and 4-9
Three steps are replaced:
Steps 1, 3, and 10 (the regulated steps!)
The new reactions provide for a spontaneous pathway (G negative in the direction of sugar synthesis), and they provide new mechanisms of regulation 6

251. Comparison of glycolysis and gluconeogenesis pathways

252. 2. Regulation of gluconeogenesis
Glycolysis and gluconeogenesis are regulated by hormones and allosteric effectors
The substrate cycle

253. (1) Gluconeogenesis is regulated by allosteric and substrate-level control mechanisms
Acetyl-CoA is potent allosteric effector of glycolysis and gluconeogenesis. Acetyl-CoA inhibits the pyruvate dehydrogenase complex (of glycolysis), but activates the pyruvate carboxylase (of gluconeogenesis).
Fructose-2,6-bisphosphate (a regulator, not an intermediate) in liver cells, signaling a high blood glucose/glucagon level, activates PFK-1 and inhibits FBPase-1.

254. (1) Gluconeogenesis is regulated by allosteric and substrate-level control mechanisms
AMP inhibits fructose 1,6-bisphosphatase (FBPase-1), but activates phosphofructokinase-1 (PFK-1).
Citrate inhibits PFK-1 and activates FBPase-1

255. Key enzymes of gluconeogenesis
PEP carboxykinase
Pyr carboxylase
Fructose-bisphosphatase
Glucose-6-phosphatase

258. F-2,6-BP activates
PFK-1, but inhibits
FBPase-1

259. The level of F-2,6-BP is controlled by the relative activity of PFK-2 and FBPase-2, which are located in one polypeptide chain and whose activities are regulated by glucagon-stimulated phosphorylation.

260. (2) Regulation of gluconeogenesis by substrate cycle
The interconversion互变现象 of two substrates catalyzed by different enzymes for single direction reactions is called “substrate cycle”.
The substrate cycle produces net hydrolysis of ATP or GTP futile cycle无效循环
当两种酶活性相等时，就不能将代谢向前推进，结果仅是ATP分解释放能量，因而又称之为无效循环=底物循环

261. Regulation of Gluconeogenesis★

262. 3. Significance of gluconeogenesis
Replenishment补给 of Glucose by Gluconeogenesis and Maintaining Normal Blood Sugar Level.
Replenishment of Liver Glycogen.
Regulation of Acid-base Balance.

263. 4、Lactic acid (Cori) cycle
Lactate, formed by the oxidation of glucose in skeletal muscle and by blood, is transported to the liver where it re-forms glucose, which again becomes available via the circulation for oxidation in the tissues. This process is known as the lactic acid cycle or Cori cycle.
prevent acidosis；reused lactate

264. Lactic acid cycle

265. Summarize for Gluconeogenesis★
What is gluconeogenesis?
Gluconeogenesis is not merely the reverse of glycolysis.
Four reactions are unique to gluconeogenesis
How gluconeogenesis is regulated?
Why gluconeogenesis is important?

266. Questions Gluconeogenesis is ( ) A The formation of glycogen
B The formation of starches
C The formation of glucose from noncarbohydrates
D The formation of glucose from other carbohydrates

267. During the gluconeogenisis conversion of pyruvate into glucose in the liver, all of the following are involved EXCEPT ( )
A pyruvate carboxylase
B phosphoenolpyruvate carboxylase
C phosphoenolpyruvate carboxykinase
D glucose 6-phosphatase
E fructose 1,6-bisphosphatase

268. Blood Sugar and Its Regulation
Section 7
Blood Sugar and Its Regulation

269. Blood Sugar
It means glucose in blood

270. 1. The source and fate of blood sugar

271. Blood sugar level must be maintained within a limited range to ensure the supply of glucose to brain.
The blood glucose concentration is 3.89～6.11mmol/L normally.
Hypoglycemia《 3.33~3.89mmol/L
Feel dizzy, tired, even coma昏迷
Hyperglycemia 》7.22~7.78mmol/L
glucosuria （糖尿）

272. 2. Regulation of blood sugar level
1）insulin： for decreasing blood sugar levels.
2）glucagon：for increasing blood sugar levels.
3）glucocorticoid糖皮质素: for increasing blood sugar levels.
4）adrenaline肾上腺素：for increasing blood sugar levels.

273. 3. Abnormal Blood Sugar Level
Hyperglycemia: > 7.22～7.78 mmol/L
The renal threshold for glucose: 8.89～10.00mmol/L
Hypoglycemia: < 3.33～3.89mmol/L

274. Pyruvate as a junction point

277. An abnormally high blood glucose level is called  
A. hypoglycemia 
B. hyperglycemia 
C. ketosis 
D. glycosis

278. Lactic acid,amino acid,glycerol
Glucogen
glycogenolysis
glycogenesis
ATP
H2O,CO2
pentose phosphate pathway
Ribose +
NADPH+H+
aerobic
glycolysis
Glucose
Pyruvate
anaerobic
digestion,
absorbtion
gluconeogenesis
Lactic acid
Starch
Lactic acid,amino acid,glycerol

279. Mitochondria is the major site for
fuel oxidation to generate ATP.