Chapter13 Additional Pathways in Carbohydrate Metabolism

Glycogen degradation and synthesis 糖原代谢与分解 Gluconeogenesis 糖异生 The pentose Phosphate pathway 磷酸戊糖途径

糖原的分解和生物合成一、糖原的分解 二、糖原的生物合成 三、糖原代谢的调控

糖原( glycogen ),又称动物淀粉，支链，分子量 数百万以上。主要由葡萄糖以 α(1,4)糖苷键相 连(93%),以少量α(1,6)糖苷键(7%)形成分 支。有肝糖原和肌糖原。

Glycogen Functions 糖原是由多个葡萄糖组成的带分枝的大分子多糖， 分子量一般在106-107道尔顿，可高达108道尔顿，是体内 糖的贮存形式，糖原主要贮存在肌肉和肝脏中，肌肉中糖 原约占肌肉总重量的1-2%约为400克，肝脏中糖原占总量 6-8%约为100克。肌糖原分解为肌肉自身收缩供给能量， 肝糖原分解主要维持血糖浓度。

Liver– Buffer for regulating blood glucose levels

Muscle– Store of glucose as a fuel for exercise high intensity exercise dependent on anaerobic glycolysis

一、糖原的酶促磷酸解 糖原的结构及其连接方式 -1,6糖苷键 非还原性末端

-1,4-糖苷键

磷酸化酶a(催化1.4-糖苷键断裂) 三种酶协同作用： 转移酶(催化寡聚葡萄糖片段转移) 脱枝酶(催化1.6-糖苷键水解断裂)

CH 2OH H H OH OH H CH 2OH H OH H OH O H OH H H O H OH CH 2OH O H OH H H O H H O H

CH 2OH O H OH H H OH H 1 O 6 CH 2 5 H OH 3 H CH 2OH O H 2 OH 1 O H H O H 4 OH H H O OH H H

glycogen

CH 2OH O H OH H H OH OH H

H O

H 4

OH

Glycogen is a polymer of glucose residues linked by (1 4) glycosidic bonds, mainly (1 6) glycosidic bonds, at branch points. Glycogen chains & branches are longer than shown. Glucose is stored as glycogen predominantly in liver and muscle cells.

Glycogen Degradation Glycogen Phosphorylase– Hydrolyzes glucose units from glycogen – Produces glucose-1-P

Removal of branch points– Debranching enzyme complex Glucan transferase Alpha-1,6-glucosidase

Glycogen catabolism (breakdown):Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the (1 4) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product. glycogen(n residues) + Pi glycogen (n–1 residues) + glucose-1-phosphate This phosphorolysis may be compared to hydrolysis: Hydrolysis: R-O-R' + HOH R-OH + R'-OH Phosphorolysis: R-O-R' + HO-PO32- R-OH + R'-O-PO32-

A glycogen storage site on the surface of the Phosphorylase enzyme binds the glycogen particle. Given the distance between storage & active sites, Phosphorylase can cleave (1 4) linkages only to within 4 residues of an (1 6) branch point. This is called a "limit branch“.

Debranching enzyme has 2 independent active sites, consisting of residues in different segments of a single polypeptide chain: The

transferase of the debranching enzyme transfers 3 glucose residues from a 4-residue limit branch to the end of another branch, diminishing the limit branch to a single glucose residue. The (1 6) glucosidase moiety of the debranching enzyme then catalyzes hydrolysis of the (1 6) linkage, yielding free glucose. This is a minor fraction of glucose released from glycogen. The major product of glycogen breakdown is glucose-1-phosphate, from Phosphorylase activity.

Enzyme-Ser-OPO32 CH2OH H OH H OH O H OH H H OPO32

Enzyme-Ser-OH CH2OPO32 O H H H H OH OPO32 OH H OH

Enzyme-Ser-OPO32 CH2OPO32 O H H H H OH OH OH H OH

glucose-1-phosphate

glucose-6-phosphate

Phosphoglucomutase catalyzes the reversible reaction: glucose-1-phosphate glucose-6-phosphate A serine OH at the active site donates & accepts Pi. The bisphosphate is not released. Phosphoglycerate Mutase has a similar mechanism, but instead uses His for Pi transfer.

Glycogen

Glucose-1-P

Glucose Hexokinase or Glucokinase Glucose-6-Pase Glucose-6-P Glucose + Pi Glycolysis Pathway

Pyruvate Glucose metabolism in liver.

Glucose-6-phosphate may enter Glycolysis or (mainly in liver) be dephosphorylated for release to the blood. Liver Glucose-6-phosphatase catalyzes the following, essential to the liver's role in maintaining blood glucose: glucose-6-phosphate + H2O glucose + Pi Most other tissues lack this enzyme.

二、糖原的生物合成1. UDP-葡萄糖焦磷酸化酶(UDP-glucose pytophosphorylase)

—— 催化单糖基活化形成糖核苷二磷酸，为各种聚糖形成 时，提供糖基和能量。动物细胞中糖元合成时需UDPG;植物 细胞中蔗糖合成时需UDPG,淀粉合成时需ADPG,纤维素合成 时需GDPG和UDPG。

2. 糖原合成酶(glycogen synthase)—— 催化 -1,4-糖苷键合成 3.糖原分支酶 ( glycogen branching enzyme)

—— 催化 -1,6-糖苷键合成

Glycogen synthesis

Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis.

As glucose residues are added to glycogen, UDP-glucose is the substrate and UDP is released as a reaction product. Nucleotide diphosphate sugars are precursors also for synthesis of other complex carbohydrates, including oligosaccharide chains of glycoproteins, etc.

糖核苷酸的生成(UDP-葡萄糖焦磷酸化酶)

+1-磷酸葡萄糖

UTP

UDPG

+PPi

在UDP-葡萄糖焦磷酸化酶作用下，1-磷酸葡萄糖生成UDP葡萄糖，消耗一个UTP,生成焦磷酸。这是一个磷酸酐交换 反应，Glu的磷酸基团带负电荷，向UTP的a-磷酸基团进攻。

UDP-glucose is formed from glucose-1-phosphate: glucose-1-phosphate + UTP UDP-glucose + PPi PPi + H2O 2 Pi Overall: glucose-1-phosphate + UTP UDP-glucose + 2 Pi Spontaneous hydrolysis of the ~P bond in PPi (P~P) drives the overall reaction. Cleavage of PPi is the only energy cost for glycogen synthesis (one ~P bond per gluc

ose residue).

糖原合成酶将UDP-葡萄糖的糖基加在糖原引物的 非还原端葡萄糖的C4羟基上。引物至少要有4个糖 基，由引发蛋白和糖原起始合成酶合成，将UDP-葡 萄糖加在引发蛋白的酪氨酸羟基上。糖原合酶 UDP+(葡萄糖)n+1

UDPG + 引物

Glycogenin initiates glycogen synthesis. Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to one of its own tyrosine residues. Glycogenin is a dimer, and evidence indicates that the 2 copies of the enzyme glucosylate one another.

Tyr active site

active site Tyr

Glycogenin dimer

6 CH

2OH

H4

5

O H OH H2

UDP-glucoseH O1

tyrosine residue of GlycogeninO C O Uridine HO C CH H2 NH O P O

OH

3

O H OH

P O 6 CH

O

2OH

O-linked H glucose residue 4OH

5

O H OH H2

H C1

O

3

O H OH

C CH H2 NH

+ UDP

CH2OH H O H H

CH2OH O H

H H C O A glycosidic bond is formedH between the anomeric C1 of H OH OH O C CH O OH H the glucose moiety derived OH from UDP-glucose and the NH H H OH hydroxyl oxygen of a tyrosine side-chain of Glycogenin. UDP is released as a product.2