lecture 14 glycolysis and gluconeogenesis (copy)

monosaccharide glucose

most common metabolic intermediates

glycolysis

is a metabolic pathway in which glucose is converted to pyruvate or lactate

gluconeogenesis

pathway achieves the reversal of glycolysis—that is, in the gluconeogenesis pathway, lactate or pyruvate are converted back to glucose.

gluconeogenesis and glycolysis

two pathways are at the core of human metabolism.

combined pathways of glycolysis and the citric acid cycle

serve as the basic energy yielding mechanisms in most organisms.

pyruvate

Under aerobic conditions, the product of glycolysis is

pyruvate, acetylCoA,

The ___ can be converted to ____ and carbon dioxide by the pyruvate dehydrogenase complex.

acetylCoA, two

The ____ is then oxidized to ___ molecules of carbon dioxide in the citric acid cycle.

glucose

has a high percentage of reduced carbon, giving it a lot of potential energy as a substrate for oxidation.

glycolysis pathway

converts glucose to pyruvate, which is the first step in oxidizing glucose to carbon dioxide.

glycolysis phase 1

one molecule of glucose (a 6 carbon compound) is converted into two molecules of glyceraldehyde-3-phosphate (a 3 carbon compound). Phase __utilizes two ATP molecules.

glycolysis phase 2

two glyceraldehyde-3-phosphate molecules are converted into two pyruvate molecules. Phase ____. generates four ATP molecules.

glycolysis structure

The six carbon hexose, glycose, is transformed into two molecules of the three carbon triose, pyruvate.

glycolysis hexose level

a single intermediate is phosphorylated at two sites, and two ATP's (2 sites X 1 ATP per site) are cleaved to two ADP's

triose level

two compounds transfer phosphate to ADP at two sites, so four ADP's (2 sites X 2 ADP's per site) are phosphorylated to four ATP's

pyruvate

f glycolysis proceeds through to ___ (aerobic metabolism), two NADH’s are produced

net balance sheet aerobic glycolysis

the metabolism of one glucose molecule results in the production of two pyruvates, two ATP’s and two NADH’s.

part 1 glycolysis

one molecule of the six carbon compound glucose is converted into two molecules of the three carbon intermediate glyceraldehyde 3-phosphate

two kinase, atp, adp

There are _____ reactions in which intermediates are phosphorylated. These reactions utilize ___ and produce ___.

part 1.2glycolysis

interconverts dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, effectively producing two molecules of glyceraldehyde 3-phosphate. This intermediate continues on down the second half of the pathway. So from here on down, there are two three-carbon molecules in the pathway. This is an important consideration when we calculate the energy balance

part 2 glycolysis

conversion of glyceraldehyde 3- phosphate to 1-3-bisphosphoglycerate, is the key to energy production by the overall pathway

part 2.2 glycolysis

This oxidation-reduction reaction not only introduces additional phosphate residues into the pathway, but also results in the production of two molecules of NADH. Under oxidative conditions, those two molecules of NADH can enter the oxidative phosphorylation scheme, which ultimately results in the net production of four molecules of ATP.

part 2.3 glycolysis

The addition of an extra phosphate residue produces a bis phosphate product, 1-3-bisphosphoglycerate. The two 1-3- bisphosphoglycerate molecules are immediately converted to two 3-phosphoglycerates with the concomitant production of two molecules of ATP.

part 2.4 glycolysis

the two ATP’s used in part I of glycolysis have been regenerated, so that initial energy price has been repaid. Two more ATP’s are produced in the last reaction of the pathway, which is catalyzed by pyruvate kinase. This means that glycolysis gives a net yield of two ATP molecules directly, with the potential for four more ATP’s from the oxidation of the two NADH’s.

pyruvate, aerobic, acetylCoA, (glycolysis reaction)

Two molecules of ___are the other end products of glycolysis. Under ____ conditions, these two pyruvate molecules are converted into ___which can then enter the TCA cycle

anaerobic glycolysis

where oxygen is rate limiting, pyruvate is converted into lactate.

ATP, phosphate, releasing (hydrolysis reaction)

___ which has a standard energy of hydrolysis of 7.3 kcal/mol, can donate a ____to the hexoses in an energy ____ reaction,

adp (glycolysis)

can accept phosphate from the trioses also in an energy releasing reaction.

all reactions in glycolysis

involve the transfer of phosphate to or from ATP have a favorable standard free energy, and thus tend to proceed in the direction of product formation.

negative, product

the overall free energy change for the conversion of glucose to carbon dioxide is highly _____. it drives the reaction pathways in the direction of _____formation.

release at least a little bit of energy.

It seems necessary that each and every reaction must

ATP, small

The reactions that produce ____ directly (substrate level phosphorylation) seem to have ____free energy changes

nucleotide, negative, small negative

the reactions that produce reduced ____ products have large ___ free energy changes. Again, every reaction must have at least a ____ free energy change, or the reactions would be going backward.

glycolysis-hexokinase

phosphate is transferred from a higher energy donor, ATP, to a lower energy product, glucose 6-P.

product, release (glucose hexinase)

The reaction proceeds in the direction of___ because the phosphoanhydride bond of ATP ____more energy than it takes to forge the phosphoester bond in glucose 6-P.

no

can phosphoralyated glucose diffuse out of the cell through the membrane and transport proteins in the plasma membrane?

low, favored

chemical transformation of glucose into glucose 6-P keeps the intracellular glucose concentration ___, so diffusion of glucose into the cell is ___.

hexokinase

most cells use ____to phosphorylate glucose

glucokinase

the liver uses enzyme_____

only works when glucose is high in the cell

high Km assures that glucokinase

high Km of glucokinase

___ allows glucose to diffuse out of liver cells into the blood. The glucose is transported from the liver and serves as an energy source for other tissues.

phase 3 glycolysis

isomerization of glucose 6- phosphate to fructose 6-phosphate catalyzed by
phosphoglucoisomerase

phase 3.1 glycolysis

aldose, glucose 6-phosphate, is converted into the ketose, fructose 6-phosphate. The open chain form of fructose 6-phosphate then undergoes mutarotation to form a cyclic furanose ring structure.

phase 4 glycolysis

fructose 6-phosphate is phosphorylated in an ATP-dependent kinase reaction, yielding fructose 1-6-bisphosphate.

gluconeogenesis pathway ( glycolysis phase. 4)

the reversal of this step is accomplished by an alternate reaction catalyzed by a different enzyme. Directly reversing this step using phosphofructokinase would be thermodynamically unfavorable.

glycolysis phase 5

one six carbon compound is converted into two three-carbon compounds. Aldolase catalyzes an aldol cleavage reaction in which the substrate is split between adjacent alcohol groups to produce two products, one an aldehyde and the other an alcohol.

glycolysis phase 5.1

new aldehyde group is found in glyceraldehyde 3-phosphate, and the alcohol group occurs in dihydroxyacetone phosphate.

triose phosphate isomerase (glycolysis phase 5)

converts
dihydroxyacetone phosphate into a second molecule of glyceraldehyde 3-phosphate. The mechanism of this isomerization is the same as that of phosphoglucoisomerase

triose phosphate isomerase part. 2 (glycolysis phase 5)

At this point in glycolysis, one molecule of glucose has been converted into two molecules of glyceraldehyde 3-phosphate. From here on, each step in the glycolysis pathway involves two identical, three carbon molecules.

combined action of the aldolase and triose phosphate isomerase

constitutes an important watershed in glycolysis

atp

doubling is what allows the glycolysis pathway to have a net yield of ___.

end of glycolysis

there are two sites at which ATP is produced, and one site where NADH is the product.

4, 2

the net result in this stage of GLYCOLYSIS is the production of ___ molecules of ATP and ___ molecules of NADH.

Glyceraldehyde 3-phosphate dehydrogenase (glycolysis)

____ introduces an extra phosphate residue into the pathway and also produces a molecule of NADH (which will ultimately yield energy)

phosphoglycerate kinase reaction(glycolysis)

____ then transfers that newly added phosphate to ADP to produce the first ATP product in the pathway

Glyceraldehyde 3-phosphate dehydrogenase (glycolysis)

____catalyzes the incorporation of an additional phosphate residue into its product, and it simultaneously carries out an oxidation-reduction reaction

NAD+, aldehyde, NADH, four, atp

The oxidation-reduction reaction uses ___ as the oxidant. In the reaction, an _____ is oxidized to an acid, and NAD+ is reduced to ____. Under aerobic conditions, the two molecules of NADH can enter the oxidative phosphorylation pathway, resulting in the net production of ____molecules of ___.

NAD+ oxidation-reduction

process involves the nicotinamide ring system, which can accept two electrons and one proton.

aerobic, high, atp

Under ___ conditions, the NADH from glycolysis is used in the oxidative phosphorylation system to provide __ energy electrons that are used to create a proton gradient across the inner membrane of the mitochondria. That gradient is then used to drive the synthesis of ___ by the ATP synthase.

phosphoglycerate kinase

catalyzes the transfer of a phosphoryl group from the mixed acid anhydride of 1,3-bisphosphoglycerate to ADP. This is the first direct energy payback in glycolysis, effectively replacing the two ATP’s that were used in the earlier steps. The other product of the reaction is 3-phosphoglycerate.

phosphorylation

process in which a phosphate residue is directly transferred from an organic phosphorylated intermediate to ADP to make ATP.

oxidative phosphorylation

uses the downhill transport of high energy electrons to form a proton gradient, which in turn is used to drive the synthesis of ATP from ADP and inorganic phosphate

phase. 6 glycolysis

converts 3-phosphoglycerate into 2- phosphoglycerate. This reaction, which is catalyzed by phosphoglyceratemutase, involves the transfer of a phosphoryl group from the number 3 carbon to the number 2 carbon of glycerate.

phase 6.1

dehydration reaction, catalyzed by enolase, in which water is removed from 2-phosphoglycerate to produce a double bond. The product of this reaction is phosphoenolpyruvate (PEP).

phosphoenolpyruvate

this compound is a phosphoenol derivative, meaning the phosphate group is adjacent to a carbon-carbon double bond. The proximity of the phosphate to the double bond gives _____ a very high negative ΔG of hydrolysis

phase 7 glycolysis

catalyzed by pyruvate kinase. accomplishes substrate level phosphorylation—a process in which ATP is formed by the direct transfer of a phosphoryl group from an organic phosphate molecule to ADP. the substrate phosphoenolpyruvate is converted to pyruvate with the transfer of a phosphate residue to ADP to form ATP.

production of two molecules of ATP by pyruvate kinase

gives glycolysis a net positive ATP yield

only occurs under aerobic conditions

four extra ATP’s can be formed from the NADH produced by glyceraldehyde 3-phosphate dehydrogenase

aerobic glycolysis

One glucose molecule yields two molecules of pyruvate.

aerobic glycolysis

-The ATP Investment is one for the hexokinase reaction and two for the phosphofructokinase reaction.

aerobic glycolysis

The ATP return is one for the phosphoglycerate kinase reaction and two for the pyruvate kinase reaction.

aerobic glycolysis

The NADH Return is two for the glyceraldehyde 3-P dehydrogenase reaction. Under aerobic conditions, these two NADH molecules can ultimately yield four molecules of ATP

aerobic glycolysis

rest or during relatively long and slow exercise

oxygen

the rate of acetylCoA oxidation is limited by

pyruvate

is diverted into a side reaction, employing lactate dehydrogenase

lactate

anaerobic conditions, the product of glycolysis is

two step pathway that produces ethanol as an end product

fermentative microorganisms such as yeast, another reaction scheme is employed under anaerobic conditions. The pyruvate is diverted into a

lactate dehydrogenase

During vigorous exercise, pyruvate is reduced to lactate

Lactate Dehydrogenase Mechanism

oxidation-reduction reaction in which the reduction of pyruvate is coupled to the oxidation of NADH. The ketone carbonyl group of pyruvate is reduced to the secondary alcohol group of lactate.

exceeds its rate of utilization by the TCA cycle

When oxygen is rate limiting, the production of pyruvate by glycolysis

NADH back to NAD+

reduction of pyruvate to lactate is coupled to the oxidation of

NAD+

This renewal of the ____ supply allows glycolysis to proceed past the glyceraldehyde 3-phosphate dehydrogenase reaction.

glycolysis

can continue unabated until the muscles start to scream from the accumulation of lactate (lactic acid).

anaerobic fermentation

______of glucose to lactate has the same direct ATP yield as the aerobic conversion of glucose to pyruvate.

anaerobic fermentation

there is no net yield of NADH because NADH is recycled to NAD+

anaerobic conditions

many microorganisms convert pyruvate to ethanol.

anaerobic

serves to regenerate NAD+ and to get rid of excess pyruvate when oxygen is not available.

Conversion of Pyruvate to Ethanol phase 1

starts with the decarboxylation of pyruvate to acetaldehyde, a reaction that is accomplished by pyruvate decarboxylase.

Conversion of Pyruvate to Ethanol phase 2

eduction of acetaldehyde to ethanol with the concomitant conversion of NADH to NAD+.

Conversion of Pyruvate to Ethanol phase 3

catalyzed by alcohol dehydrogenase. The NAD+ is used in further rounds of glycolysis, and the ethanol is excreted from the cell. In a closed system such as yeast fermentation, the ethanol rises to levels where it can eventually kill the cells.

lactate fermentation

Ethanol fermentation has the same net energy balance as

Net Yield for Ethanol Fermentation

giving a net yield of 2 ATP's with no net production of NADH.

Invertase Reaction

conversion of the disaccharide sucrose into glucose and fructose by the enzyme invertase.glucose formed in the reaction enters directly into glycolysis.

Entry of Fructose into Glycolysis. step. 1

first step is catalyzed by fructokinase, which transfers a phosphoryl group from ATP to the number C-1 of fructose. Fructose 1-phosphate has a phosphoester bond with relatively low energy of hydrolysis, so the transfer of a phosphoryl group from ATP is thermodynamically favorable.

Entry of Fructose into Glycolysis. step. 2

pathway is catalyzed by an aldolase, which is specific for fructose 1-phosphate. The products of this aldol cleavage reaction are dihydroxyacetone phosphate and glyceraldehyde. The glyceraldehyde is phosphorylated by a triose kinase to give glyceraldehyde 3-phosphate.

completes the integration of fructose into glycolysis

The production of dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. It takes two ATP’s to integrate fructose into glycolysis—one to phosphorylate fructose and one to phosphorylate glyceraldehyde.

lactose into galactose and glucose.

enzyme lactase cleaves

Entry of Galactose into Glycolysis. step. 1

Galactose is first phosphorylated by galactose kinase. The product, galactose 1-phosphate, is converted into glucose 1-phosphate by an exchange reaction involving the sugar nucleotide, UDP-glucose.

Entry of Galactose into Glycolysis. step 2

Phosphoglucomutase then catalyzes the isomerization of glucose 1-phosphate to glucose 6-phosphate. At that point, the compound is integrated into glycolysis.

conversion of galactose 1-phosphate to glucose 1-phosphate

1-phosphate is exchanged for galactose 1-phosphate. UDP-glucose (Uridine diphosphate glucose) picks up galactose 1-phosphate and releases glucose 1-phosphate. UDP-galactose is the other product.