2 glycolysi-gluconeogenesis

III-II Carbohydrate metabolism

III-III Lipid metabolism

III-V Protein turnover and amino acid metabolism

III-IV TCA cycle and biological oxidation

III-VI Regulation of the metabolic pathways

III-I Metabolism


1. Digestion and absorption of dietary carbohydrates2. Pathways of glucose metabolism: glycolysis3. Galactose and fructose metabolism 4. Gluconeogenesis5. Glycogenolysis, glycogenesis6. Glycogen storage disease7. Pentose phosphate shunt8. Inborn errors of glucose metabolism9. Regulation of glucose metabolism.

Why do we need carbohydrate ?

AA

QQ

The most important energy-rich molecules, energy-rich molecules, as

well as building blocksbuilding blocks of biomolecules......

Most abundant in living cells

monosaccharide

aldose

disaccharide

polysaccharide

After eat, what will happen with carbohydrate?

AA

QQ

digestion absorption metabolism

as well as lipids and proteins

Digestion of carbohydrates

ploysaccharide monosaccharide

enter into cell

A family of transporters enables glucoseto enter and leave animal cells, GLUT 1-5

Absorption of carbohydrates


1. Digestion and absorption of dietary carbohydrates2. Pathways of glucose metabolism: glycolysis3. Galactose and fructose metabolism4. Gluconeogenesis5. Glycogenolysis, glycogenesis6. Pentose phosphate shunt7. Glycogen storage disease8. Inborn errors of glucose metabolism9. Regulation of glucose metabolism.

Why do we talk about the glucose?

AA

QQ

The glucose, common constituent of carbohydrates,

is an iimportant and common fuelmportant and common fuel, with a key

position in carbohydrates metabolism,

Classification of carbohydrates

In mammals, glucose is the only fuel that the the only fuel that the brain uses under nonstarvation conditionsbrain uses under nonstarvation conditions and the only fuel that red blood cells can use at allthe only fuel that red blood cells can use at all.

Indeed, almost all organisms use glucosealmost all organisms use glucose, and most that do process it in a similar fashionin a similar fashion.

Furthermore, some monosaccharides are some monosaccharides are processed by entry into glucose metabolic processed by entry into glucose metabolic pathwaypathway.

blood glucose

Major pathways in carbohydrate metabolism

glucoseaerobic oxidation

anaerobic oxidation

glycogen

ATPreducing power building blocks

de novo synthesis

aerobic oxidation of glucose

lactic acid fermentation

alcoholic fermentation

anaerobic oxidation of glucoseglucose

no O2

more energy, but take longer time

by the way

Indeed, many food products are the result of fermentations. These foods include sour cream, yogurt, various cheeses, beer, wine, and sauerkraut.

by the way

QQWhat is the glycolysis?

GlycolysisGlycolysis is the sequence of reactions that metabolizes one molecule ofone molecule of glucoseglucose to two molecules of pyruvate two molecules of pyruvate with the concomitant net production of two net production of two molecules of ATPmolecules of ATP.

glycolysis, an ancient energy-energy-conversion conversion pathway employed by a host of organisms.

AA

Some fates of glucose

something happen

The process of glycolysisThe process of glycolysis

AA

QQ

The glycolytic pathway has a dual role: it The glycolytic pathway has a dual role: it degrades glucose to generate ATPdegrades glucose to generate ATP, and it , and it provides building blocks for the synthesisprovides building blocks for the synthesis of of cellular components. cellular components.

What is the role of the glycolysis?

From glucose to pyruvate, there are 10 From glucose to pyruvate, there are 10 steps, divided into 3 stages, occurred in steps, divided into 3 stages, occurred in cytosol. cytosol.

AA

QQWhat is the course of glycolysis?

Stage 1Stage 1, which is the conversion of glucose into fructose 1,6-bisphosphate. The strategy of these initial steps in glycolysis is tto trap the glucose in the o trap the glucose in the cellcell and and form a compound that can be form a compound that can be readily cleaved into phosphorylated readily cleaved into phosphorylated three-carbon units.three-carbon units.

Stage 2Stage 2 is the cleavage of the fructose 1,6-bisphosphate into two three-carbon fragments. These resulting resulting three-carbon three-carbon unitsunits are readily interconvertible.

Stage 3Stage 3, ATP is harvestedATP is harvested when the three-carbon fragments are oxidized to pyruvate.

General description of glycolysisGeneral description of glycolysis


Two ATP molecules are needed . Two ATP molecules are needed .

consists of three steps:

• phosphorylationphosphorylation • isomerizationisomerization • second phosphorylationsecond phosphorylation

stage 1The process of glycolysisThe process of glycolysis


requires Mg2 +

KinasesKinases are enzymes that catalyze the transfer of transfer of a phosphoryl groupa phosphoryl group from ATP to an acceptor.


building block metabolic intermediate

(1) glucose 6-phosphate cannot diffuse cannot diffuse through

the membrane, because of its negative charges

(2) the addition of the phosphoryl group begins to

destabilize glucose, thus facilitating its facilitating its

further metabolismfurther metabolism.

Notable for two reasons to trap the glucose

in the cell

use ATP as expense


QQ

Why is glucose-6-phosphate an important intermediate?

AA

Find out and summarizeFind out and summarize by yourself.by yourself.


The isomerization of glucose 6-phosphate to fructose 6-phosphate is a conversion of an aldose into a ketose conversion of an aldose into a ketose.

The reaction catalyzed by phosphoglucose isomerase includes additional steps because both glucose 6-phosphate and fructose 6-phosphate are present primarily in the cyclic forms. The enzyme must first open the six-membered ring of glucose 6-phosphate, catalyze the isomerization, and then promote the formation of the five-membered ring of fructose 6-phosphate.


by the way


The prefix bisbis- in bisphosphate means that two separate monophosphate groupstwo separate monophosphate groups are present, whereas the prefix didi- in diphosphate (as in adenosine diphosphate) means that two phosphate groups are present and are connected by an anhydride two phosphate groups are present and are connected by an anhydride bondbond.

This reaction is catalyzed by phosphofructokinase (PFK), an allosteric enzymeallosteric enzyme that sets the pace of glycolysis.

This enzyme plays a central role in the integration of much of metabolism


the cleavage of the fructose 1,6-bisphosphate into two three-carbon fragments.These resulting three-carbon unitsresulting three-carbon units are readily interconvertible.

consists of two steps

• cleavage

• isomerization


The products of the remaining steps in glycolysis consist of three-carbon unitsthree-carbon units rather than six-carbon unitssix-carbon units.

The reaction catalyzed by aldolase is readily reversible under intracellular conditions.

readily reversible under intracellular conditions.

2X 3C unit


The isomerization of these three-carbon phosphorylated sugars is catalyzed by triose phosphate isomerase. This reaction is rapid and reversible.

an intramolecular oxidation–reduction.an intramolecular oxidation–reduction.

DHAP GAP


ATP is harvestedATP is harvested when the three-carbon fragments are oxidized to pyruvate.


consists of five steps • Oxidation• Transfer of a phosphate groupTransfer of a phosphate group• Isomerization• Dehydration• Transfer of a phosphate groupTransfer of a phosphate group


1,3-Bisphosphoglycerate is an acyl phosphate. Such compounds

have a high phosphoryl-transfer potentialhave a high phosphoryl-transfer potential; one of its phosphoryl

groups is transferred to ADP transferred to ADP in the next step in glycolysis.

The reaction catalyzed by glyceraldehyde 3-phosphate dehydrogenase is really the sum of two processes: the oxidation of the aldehydealdehyde to a carboxylic acidcarboxylic acid by NAD and the joining of the carboxylic acid and orthophosphate to form the acyl-phosphate product.

The process of glycolysisThe process of glycolysisby the way

The first reaction is quite thermodynamically favorable thermodynamically favorable with a standard free-energy change, G°, of approximately 12 kcal mol1 (50 kJ mol1), whereas the second reaction is quite unfavorable quite unfavorable with a standard free-energy change of the same magnitude but the opposite sign.

These two processes must be coupledThese two processes must be coupled so that the favorable aldehyde oxidation can be used to drive the formation of the acyl phosphate. How are these reactions coupled? The key is an intermediate, formed as a result of the aldehyde oxidation, that is higher in free energy than the free carboxylic acid is. This intermediate reacts with orthophosphate to form the acyl-phosphate product.

The process of glycolysisThe process of glycolysis by the way

Free-energy profiles for glyceraldehyde oxidation followed by acyl-phosphate formation.

(A) A hypothetical case with no coupling between the two processes. The second step must have a large activation barrier, making the reaction very slow.

(B) The actual case with the two reactions coupled through a thioester intermediate. thioester intermediate.

The process of glycolysisThe process of glycolysisby the way


1st substrate-level phosphorylation

The phosphate donor, 1,3-BPG, is a substrate with high phosphoryl-transfer potential.

The formation of ATP in this manner is referred to as substrate-level phosphorylationsubstrate-level phosphorylation

oxidative phosphorylation


1. Glyceraldehyde 3-phosphate, an aldehyde, is oxidized to 3-phosphoglycerate, a carboxylic acid.

2. NAD is concomitantly reduced to NADHNAD is concomitantly reduced to NADH.

3. ATP is formed from Pi and ADPATP is formed from Pi and ADP at the expense of carbon oxidation energy.

The outcomes of the reactions catalyzed by glyceraldehyde 3-phosphate dehydrogenase and phosphoglycerate kinase are:



The position of the phosphoryl group shifts in the conversion of 3-3-phosphoglycerate phosphoglycerate into 2-phosphoglycerate2-phosphoglycerate, a reaction catalyzed by phosphoglycerate mutasephosphoglycerate mutase. In general, a mutase is an enzyme that catalyzes the intramolecular the intramolecular shift of a chemical groupshift of a chemical group, such as a phosphoryl group.



Enolase catalyzes the formation of phosphoenolpyruvate (PEP).This dehydration markedly elevates elevates the transfer potential of the phosphoryl groupthe transfer potential of the phosphoryl group.. An enol phosphate has a high phosphoryl-transfer potential enol phosphate has a high phosphoryl-transfer potential, whereas the phosphate ester, such as 2-phosphoglycerate, of an ordinary alcohol has a low one.



1st substrate-level phosphorylation

2nd substrate-level phosphorylation


enol–ketone conversion.

Why does phosphoenolpyruvate have such a high phosphoryl-transfer potential? The phosphoryl group traps the molecule in its unstable enol formits unstable enol form. When the phosphoryl group has been donated to ATP, the enol undergoes a conversion into the more stable ketone—namely, pyruvate.

The net reaction in the transformation of glucoseglucose into pyruvatepyruvate is:

Only two ATP molecules are produced.

How can a body get more ATP? from aerobic oxidation

III-IV

The net reaction in the transformation of glucoseglucose into pyruvatepyruvate is:

Two NAD+ are used.

How is NAD+ regenerated? maintain redox balancemaintain redox balance

from different ways

Pyruvate must continue its way to metabolize.

The sequence of reactions from glucose to pyruvate from glucose to pyruvate is similaris similar in most organisms and most types of cells.In contrast, the fate of pyruvate is variable. the fate of pyruvate is variable. The presence of plentiful O2 is determinant other than organisms.

AA

QQWhere does pyruvate go?

EthanolEthanol and lactatelactate can be formed by reactions involving NADNAD++.

Alternatively, a two-carbon unit from pyruvate can be coupled to coenzyme A a two-carbon unit from pyruvate can be coupled to coenzyme A

to form acetyl CoAto form acetyl CoA, which will enter into the citric acid cycle.

Three reactions of pyruvate are of prime importance: conversion into ethanol ethanol, lactic acidlactic acid, or carbon dioxidecarbon dioxide

anaerobic glycolysis

anaerobic alcoholic

fermentation

aerobic oxidation

Diverse fates of pyruvate

anaerobic lactic acid fermentation

EthanolEthanol is formed from pyruvatepyruvate in yeastyeast and several other microorganismsmicroorganisms.

There is no net oxidation–reduction in the conversion of glucose into ethanol

The regeneration of NAD in the reduction of pyruvate to ethanol sustains the continued operation of glycolysis sustains the continued operation of glycolysis under under anaerobic conditionsanaerobic conditions.

LactateLactate is formed from pyruvate in a variety of microorganisms microorganisms in a process called lactic acid fermentationlactic acid fermentation.

The regeneration of NAD in the reduction of pyruvate to lactate sustains the continued operation of glycolysis under anaerobic conditionsunder anaerobic conditions.

The reaction also takes place in the cells of higher higher organisms organisms when the amount of oxygen is limitingthe amount of oxygen is limiting, as in musclein muscle during intense activity.

Cori cycle

Only a fraction of the energy of glucose is released in

its anaerobic conversionanaerobic conversion into ethanol or lactate.

Much more energy can be extracted aerobically by means of

the citric acid cycle the citric acid cycle and the electron-transport chainthe electron-transport chain. The

entry point to this oxidative pathway is acetyl coenzyme A acetyl coenzyme A

(acetyl CoA),(acetyl CoA), which is formed inside mitochondria mitochondria by the

oxidative decarboxylation of pyruvate.

produced in

cytosolcytosol

What will happen next?

III-IV

QQ What is the most important What is the most important significance of glycolysis?significance of glycolysis?

the most important significance of glycolysis is to provide energy rapidlyto provide energy rapidly, as well as to provide energy under anaerobic conditionto provide energy under anaerobic condition,

Although, glycolysis provides limited energy,

which are absolutely necessarily for some tissuetissue, cellcell, or some situation.situation.

Who? when?

AA

The rate of conversion of glucose into pyruvateglucose into pyruvate is regulated to meet two major cellular needs: (1) the production of ATP, generated by the degradation of glucose, (2) the provision of building blocks for synthetic reactions (carbon

skeletons).

AA

QQHow is the glycolytic pathway controlled ?How is the glycolytic pathway controlled ?

QQWhere are the key points for glycolytic Where are the key points for glycolytic

pathway regulation ?pathway regulation ?

hexokinase, phosphofructokinase, and pyruvate kinase

AA

In metabolic pathways, enzymes catalyzing enzymes catalyzing essentially irreversible reactions are potential sites of essentially irreversible reactions are potential sites of controlcontrol.

In glycolysis, the reactions catalyzed by hexokinasehexokinase, phosphofructokinasphosphofructokinasee, and pyruvate kinasepyruvate kinase are virtually irreversible; hence, these enzymes would be expected to have regulatory as well as catalytic roles.

In fact, each of them serves as a control sitecontrol site.

pyruvate kinase

hexokinase

phosphofructokinase

• allosteric effectors

• covalent modification

• regulation of transcription

milliseconds

seconds

hours

pyruvate kinasehexokinase phosphofructokinase

Their activities are regulated by the reversible binding of reversible binding of allosteric effectorsallosteric effectors or by covalent modificationcovalent modification. In addition, the amounts of these important enzymes are varied by the regulation regulation of transcriptionof transcription to meet changing metabolic needs.

hexokinase

Hexokinase, the enzyme catalyzing the first step of

glycolysis, is inhibited by its product, glucose 6-phosphate.inhibited by its product, glucose 6-phosphate.

feedback inhibit

High concentrations of this molecule

signal that the cell no longer cell no longer

requires glucose for energyrequires glucose for energy, for

storage in the form of glycogenglycogen, or

as a source of biosynthetic biosynthetic

precursorsprecursors, and the glucose will be

left in the blood.

Glucose 6-phosphate is an important Glucose 6-phosphate is an important building block and metabolic intermediatebuilding block and metabolic intermediate

phosphofructokinase

is the most important control element in the mammalian glycolytic pathway

Allosteric regulation of phosphofructokinase by citratecitrate,

fructose 2,6-bisphosphatefructose 2,6-bisphosphate, fructose 1,6-bisphosphatefructose 1,6-bisphosphate, ATPATP, AMPAMP

A high level of ATP inhibits the enzyme by decreasing its affinity for substrate fructose 6-phosphate. AMP diminishes and citrate enhances the inhibitory effect of ATP.

ATP/AMP ratio

citric acid cycle

product

Glycolysis is stimulated as the Energy Charge Energy Charge falls.

Activation of phosphofructokinase by fructose 2,6-bisphosphate. (A) The sigmoidal dependence of velocity on substrate concentration becomes hyperbolic in the presence of 1 M fructose 2,6-bisphosphate.(B) ATP, acting as a substrate, initially stimulates the reaction. As the concentration of ATP increases, it acts as an allosteric inhibitorallosteric inhibitor. The inhibitory effect of ATP is reversed The inhibitory effect of ATP is reversed by fructose 2,6-bisphosphate.by fructose 2,6-bisphosphate.

Fructose 2,6-bisphosphate (F-2,6-BP) was identified as a potent activator of phosphofructokinase in 1980. Fructose 2,6-bisphosphate activates phosphofructokinase by increasing its affinity for fructose 6-phosphateincreasing its affinity for fructose 6-phosphate and diminishing the inhibitory effect of ATPdiminishing the inhibitory effect of ATP

by the way

Fructose 2,6-bisphosphate is formed in a reaction catalyzed by phosphofructokinase 2 (PFK2), a different enzyme from phosphofructokinase. Fructose 2,6-bisphosphate is hydrolyzed to fructose 6-phosphate by a specific phosphatase, fructose bisphosphatase 2(FBPase2). The striking finding is that both PFK2 and FBPase2 are present in a single 55-kd polypeptide chain

by the way

bifunctional enzyme

kinase & phosphatase

Why is phosphofructokinase rather than hexokinase the pacemaker of glycolysis?

The reason becomes evident on noting that glucose 6-phosphate is glucose 6-phosphate is not solely a glycolytic intermediate.not solely a glycolytic intermediate. Glucose 6-phosphate can also be converted into glycogenglycogen or it can be oxidized by the pentose pentose phosphate pathwayphosphate pathway to form NADPH.

The first irreversible reaction unique to the glycolytic pathwayunique to the glycolytic pathway, the committed stepcommitted step, is the phosphorylation of fructose 6-phosphate to the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphatefructose 1,6-bisphosphate. Thus, it is highly appropriate for phosphofructokinase to be the primary control site in glycolysisthe primary control site in glycolysis.

In general, the enzyme catalyzing the committed stepthe committed step in a metabolic sequence is the most important control element in the pathway.

Pyruvate kinase, the enzyme catalyzing the third irreversible step in glycolysis, controls the outflow from this pathway.controls the outflow from this pathway.

This final step yields ATP and pyruvatepyruvate, a central metabolic intermediate a central metabolic intermediate that can be oxidized further or used as a building block.

pyruvate kinase

Control of the catalytic activity of pyruvate kinase. Pyruvate kinase is regulated by allosteric allosteric effectors and covalent covalent modification.

Key concept map of glycolysis

energy metabolism

Glycolysis is one of the essential pathways of energy metabolism

Summarize Summarize

QQ AA&&

by yourself by yourself



Galactose and fructose will enter into GLYCOSIS in certain points.enter into GLYCOSIS in certain points.

AA

QQWhat other monosaccharides will do ?What other monosaccharides will do ?

C-2 and C-4 epimersepimers and an isomer isomer of glucose

presence of the chiral carbon

presence of different functional groups

aldose

ketose

There are no catabolic pathways to metabolize galactose, so the strategy is to convert galactose to convert galactose into a metabolite of glucoseinto a metabolite of glucose, glucose 6-phosphateglucose 6-phosphate.

isomerized to

glucose 6-phosphateglucose 6-phosphate by phosphoglucomutase.

Galactose metabolism.

an important intermediate

Fructose metabolismFructose enters the glycolytic pathway in liverin liver through the fructose 1-phosphate pathway the fructose 1-phosphate pathway.

Most of the fructose in adiposein adipose tissuetissue is metabolized throughfructose 6-phosphate fructose 6-phosphate by hexokinase.

different tissues, different metabolic pathway

Many adults are intolerant of milk because they aredeficient in LactaseLactase

disaccharide monosaccharide

Abnormal lactose

metabolism

EXAMPLE

The brain depends on glucose as its primary fuelprimary fuel. The red blood cells use glucose as only fuelonly fuel.

In a typical adult human being, the daily glucoseglucose requirement of the brain brain is about 120g120g, glucoseglucose needed daily by the whole body whole body is 160g.160g.

The amount of glucoseglucose present in body fluids is about 20g20g, readily available from glycogenfrom glycogen is approximately 190g190g.

Thus, the direct glucose reserves direct glucose reserves are sufficient to meet glucoseglucose needs for about a day a day.

During a longer period of starvation, glucose must be formed from noncarbohydrates sources for some tissues use.



The glucose could be synthesized from noncarbohydrate noncarbohydrate precursorsprecursors in the process of in the process of gluconeogenesisgluconeogenesis..

AA

QQHow is the glucose formed from

noncarbohydrate sources?

glucoseaerobic oxidation

anaerobic oxidation

glycogen

ATPreducing power building blocks

de novo synthesis

The gluconeogenic pathway converts pyruvatepyruvate into glucose.glucose.

pyruvate glucose→→ → → →

gluconeogenesis

glycolysis

Gluconeogenesis is not a reversal of glycolysisGluconeogenesis is not a reversal of glycolysis

AA

QQWhere does the gluconeogenesis

take place?

The major site of gluconeogenesis is the LIVERLIVER, with a small amount also taking place in the KIDNEYKIDNEY..

Erythocytes, brain use glucose as their solesole or primary energy sourceprimary energy source, but they cannot synthesize itcannot synthesize it.

different tissues, different metabolic pathways

Gluconeogenesis in the liver and kidney helps to

maintain the glucose level in the bloodmaintain the glucose level in the blood .

so that BRAINBRAIN and MUSCLEMUSCLE can extract sufficient can extract sufficient

glucose from itglucose from it to meet their metabolic demands.

Metabolic coordination is on the level of whole body.

QQWhat are the major precursors

for gluconeogenesisluconeogenesis ?

The major noncarbohydrate precursors are lactatelactate, amino acidsamino acids, and glycerolglycerol.

hydrolysis of fatfrom protein degradation

formed by active skeletal muscle when the rate of glycolysis

exceeds the rate of oxidative exceeds the rate of oxidative metabolism.metabolism.

Cori Cycle

AA

The Cori CycleCori Cycle shifts part of the metabolic burdenmetabolic burden of active muscle to the liver.

The liver furnishes glucose to contracting skeletal muscleliver furnishes glucose to contracting skeletal muscle, which derives ATP from the glycolytic conversion of glucose into lactate. Contracting skeletal muscle supplies lactate to the liver,Contracting skeletal muscle supplies lactate to the liver, which uses it to synthesize glucose.

There are three distinctive reactions and their related distinctive reactions and their related enzymesenzymes . The other reactions are common to glycolysis.common to glycolysis.

AA

QQWhat is the course of gluconeogenesis?

The enzymes for gluconeogenesisare located in the cytosol cytosol, except for pyruvate carboxylase (in the mitochondria mitochondria) and glucose 6-phosphatase (membrane bound in the endoplasmic reticulumendoplasmic reticulum).

The distinctive reactions and enzymes of this The distinctive reactions and enzymes of this pathway are shown in pink. pathway are shown in pink. The other reactions are common to glycolysis.common to glycolysis.

The whole process of gluconeogengsis is finished in cytosolcytosol, mitochondriamitochondria, and endoplasmic reticulumendoplasmic reticulum..

Pathway of Gluconeogenesis

Distinctive reaction compare with glycolysis

In gluconeogenesisIn gluconeogenesis, there must be some new steps bypassbypass above virtually irreversible reactions of glycolysis:

pyruvate kinase

hexokinase

phosphofructokinase

The actual ∆G for the formation of pyruvate from glucose is about -20 kcal mol-1 (-84 kJ mol-1) under typical cellular conditions. Most of the decrease in free energy in glycolysis takes place in the three essentially irreversible steps catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase.Gluconeogenesis

in glycolysis

There are two steps from pyruvatepyruvate to phosphoenolpyruvate.phosphoenolpyruvate.

Compartmental cooperation. OxaloacetateOxaloacetate utilized in the cytosol for gluconeogenesis is formed in the mitochondrial mitochondrial matrix matrix by carboxylation of pyruvate.Oxaloacetate leaves the mitochondrion by a specific transport system (not shown) in the form of malatemalate,which is reoxidized to oxaloacetate in the cytosolcytosol.

glycolysis in cytosol

In most tissues, gluconeogenesis ends here. In most tissues, gluconeogenesis ends here. G-6-P enters into glycolysis directly.G-6-P enters into glycolysis directly.

Free glucose is not generated; rather, the glucose 6-phosphate is processed in some other fashion, notably to form glycogenglycogen. Another advantage to ending gluconeogenesis at glucose 6-phosphate is that, unlike free glucose, the molecule cannot diffuse out of the cellthe molecule cannot diffuse out of the cell.

The reaction is controlled.

Generation of glucose from glucose 6-phosphate

Glucose 6-phosphate is transported into the lumen lumen of the endoplasmic reticulumof the endoplasmic reticulum, where it is hydrolyzed to glucose by glucose 6-phosphataseglucose 6-phosphatase, which is bound to the membrane.

To keep glucose inside the cell, the generation of free glucose is controlled in two ways.First, the enzyme responsible for the conversion of glucose 6-the enzyme responsible for the conversion of glucose 6-phosphate into glucose,phosphate into glucose, glucose 6-phosphatase, is regulated glucose 6-phosphatase, is regulated. Second, the enzyme is present the enzyme is present only in tissues whose metabolic only in tissues whose metabolic duty is to maintain blood-glucose homeostasis—tissuesduty is to maintain blood-glucose homeostasis—tissues that release glucose into the blood. These tissues are the liver and to a lesser extent the kidney.

Chapter III

ATP hydrolysis is used to power an energetically unfavorable reaction.

Gluconeogenesis

reverse of glycolysis an energetically unfavorable process

GlycerolGlycerol may enter either the gluconeogenesis (DHAPDHAP)or the glycolysis at dihydroxyacetone phosphate.

glycolysisglycolysis GluconeogenesisGluconeogenesis

Different precursors enter into gluconeogenesis at different entry poins

glucogenic amino acids

Gluconeogenesis and glycolysis are Gluconeogenesis and glycolysis are reciprocally regulated

AA

QQHow are gluconeogenesisgluconeogenesis and glycolysis glycolysis

coordinated?

Gluconeogenesis and glycolysis are coordinated so that within a cell one pathway is relatively inactive one pathway is relatively inactive while the other is highly activewhile the other is highly active.

the amountsamounts and activitiesactivities of the distinctive enzymes of distinctive enzymes of each pathwayeach pathway are controlled so that both pathways are not highly active at the same time.

Reciprocal regulation of gluconeogenesis and glycolysis in the

liver.

The interconversion of fructose 6-phosphatefructose 6-phosphate and fructose 1,6-bisphosphatefructose 1,6-bisphosphateis stringently controlled

The interconversion of phosphoenolpyruvatephosphoenolpyruvate and pyruvatepyruvate also is preciselyregulated.

Glycolysis and gluconeogenesis are coordinated in a tissue-in a tissue-specific fashionspecific fashion, to ensure that the glucose-dependent energy needs of all cells are met.

Cooperation between glycolysis and gluconeogenesis

Key concept map for gluconeogenesis

GlycolysisGlycolysis is the set of reactions that converts glucose into pyruvate. The 10 reactions of glycolysis take place in the cytosol. There is a net gain of two molecules of ATP in the formation of two molecules of pyruvate from one molecule of glucose.

The electron acceptor in the oxidation of glyceraldehyde 3-phosphate is NAD, which must be regenerated for glycolysis to continue.

SummarySummary for Glycolysis and gluconeogenesis

Under physiologic conditions, the reactions of glycolysis are readily reversible except for the ones catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase.

The glycolytic pathway has a dual role: it degrades glucose to generate ATP, and it provides building blocks for the synthesis of cellular components. The rate of conversion of glucose into pyruvate is regulated to meet these two major cellular needs.

GluconeogenesisGluconeogenesis is the synthesis of glucose from noncarbohydrate sources, such as lactate, amino acids, and glycerol.

Several of the reactions that convert pyruvate into glucose are common to glycolysis. Gluconeogenesis, however, requires four new reactions to bypass the essential irreversibility of three reactions in glycolysis.

The major raw materials for gluconeogenesis by the liver are lactate and alanine produced from pyruvate by active skeletal muscle. The formation of lactate during intense muscular activity buys time and shifts part of the metabolic burden from muscle to the liver.

GluconeogenesisGluconeogenesis and glycolysisglycolysis are reciprocally regulated so that one pathway is relatively inactive while the other is highly active.

Summarize Summarize

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DHAP GAP

1,3-bis-P-glycerate

3-P-glycerate

2-P-glycerate

PEP

F-1,6-bis-P

F-6-P

G-6-P

pyruvate lactate

G

gluconeogenesis

gluconeogenesis

glycerol

fructose

galactose

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2 glycolysi-gluconeogenesis