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Gluconeogenesis. Triacylglycerol hydrolysis .  i s not a reversal of glycolysis  n oncarbohydrate precursors of Glc, carbon skeleton  t ake place in liver , minor in kidney, brain, skeletal and heart muscle, to maintain the Glc level in the blood

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gluconeogenesis
Gluconeogenesis

Triacylglycerol

hydrolysis

 is not a reversal of glycolysis

 noncarbohydrate precursors of Glc, carbon skeleton

 take place in liver, minor in kidney, brain, skeletal and heart muscle, to maintain the Glc level in the blood

 Glc is the primary fuel of brain, and the only fuel of red blood cells

protein breakdown 

active skeletal muscle 

slide5

G°´

0.7

-0.5

- 7.5 kcal/mol

glycolysis vs gluconeogenesis
Glycolysis vs. Gluconeogenesis

¤Three irreversible reactions, irrespective

Glycolysis:

hexokinase, phosphofructokinase, pyruvate kinase

Gluconeogenesis:

glucose 6-phosphatase, fructose 1,6-bisphosphatase,

pyruvate carboxylase, phosphoenolpyruvate carboxykinase

the stoichiometry of glycolysis vs gluconeogenesis
The stoichiometry of Glycolysis vs. Gluconeogenesis

¤Glycolysis:

Glucose + 2 ADP + 2 Pi + 2 NAD+

 2 Pyr + 2 ATP + 2 NADH + 2H+ + 2 H2O

G0’= - 20 kcal / mol

if reverse?

¤Gluconeogenesis:

2 Pyr + 4 ATP + 2 GTP + 2 NADH + 6 H2O

 Glucose + 4 ADP + 2 GDP + 6 Pi + 2 NAD+ + 2H+

G0’= - 9 kcal / mol

NTP hydrolysis is used to power an energetically unfavorable reaction

Both reactions are exergonic

compartmental cooperation mitochondrial
Compartmental cooperation- mitochondrial

Pyruvate carboxylaseMito

NADH-malate dehydrogenase

G0’

decarboxylation

Specific transporter

NAD+-malate dehydrogenase

GTP

PEP + CO2

PEP carboxykinase

pyruvate carboxylase pyr co 2 atp h 2 o oaa adp p i 2 h
Pyruvate carboxylase(Pyr + CO2 + ATP + H2O OAA + ADP + Pi + 2 H+)

(ATP-activating

domain, p. 711)

The onlymitochondrial enzymes among the enzymes of gluconeogenesis

Carbonic anhydrase

HCO3-+ ATP  HOCO2-PO32- + ADP carboxyphosphate: activated form of CO2

Biotin-Enz + HOCO2-PO32-  CO2-biotin-Enz + Pi is activated by acetyl CoA (p. 493)

CO2-biotin-Enz + Pyr  biotin-Enz + OAA

S

-amino group of Lys

(PCase)

free glucose generation
Free glucose generation

(Does not take place in cytoplasm)

F1,6bisP  F6P  G6P•••  Glc

The endpoint of gluconeogenesis in most tissues,

can keep Glc or G6P is converted into glycogen.

In liver and to a lesser extent the kidney,

five proteins are involved

SP: a calcium-binding stabilizing protein

Gluconeogenesis 

reciprocal control glycolysis and gluconeogenesis are not highly active at the same time

p. 465

Reciprocal control:Glycolysis and gluconeogenesis are not highly active at the same time

– Energy state

– Intermedia:

allosteric effectors

– Regulators:

hormones

 Amounts and activities

of distinctive enzymes

Starvation:

glucagon

rich in precursors

high energy state

Fed state:

insulin

low energy state

biofunctional of phosphofructokinase 2 phosphofructokinase fructose bisphosphatase 2 f6p f2 6bisp
Biofunctional of phosphofructokinase 2phosphofructokinase / fructose bisphosphatase 2F6P  F2,6BisP

Janus

a single 55-kd polypeptide chain

L (liver) / M (muscle) isoforms

slide13

Fructose 2,6-bisphosphate: synthesis and degradation

PEP carbokinase 

F 1,6-bisphosphatase 

Glycolytic enzymes 

(pyruvate kinase)

In liver:

the first irreversible reaction of glycolysis glc g6p
The first irreversible reaction of glycolysis:Glc  G6P

¤Hexokinase: is inhibited by G6P

Km of sugars: 0.01 ~ 0.1 mM

Glucokinase: not inhibited by G6P

Km of glucose: ~10 mM

present in liver, to monitor blood-glucose level.

¤Committed step

the most important control step in the pathway

G6P glycogen biosynthesis

 fatty acid biosynthesis

 pentose phosphate pathway

hormones
Hormones

¤Affect the expression of the gene of the essential enzymes

– change the rate of transcription

– regulate the degradation of mRNA

¤ allosteric control (~ms); phosphorylation control (~ s);

transcription control (~ h to d)

The promoter of the PEP carboxykinase (OAAPEP) gene

IRE: insulin response element;

GRE: glucocorticoid response element

TRE: thyroid response element

CRE: cAMP response element

substrate cycle futile cycle
Substrate cycle (futile cycle)

Biological significances

Simultaneously fully active

(1) Amplify metabolic signals

(2) Generate heat

bumblebees:

PFKase

F1,6-bisPTase:

is not inhibited by AMP

honeybees:onlyPFKase (02)

malignant hyperthermia

If  10

cori cycle
Cori cycle:

Contracting skeletal muscle supplies lactate to the liver, which uses it to synthesize and release glucose

+ NADH

Ala

Ala

transaminase

+ NAD+

carriers

Absence of O2

Pyr

Lactate

Ala metabolism:

maintain nitrogen balance

Well-oxygenated

TCA cycle

lactate dehydrogenase
Lactate dehydrogenase

¤a tetramer of two kinds of 35-kd subunits encoded by similar genes

¤H type: in heart (muscle)

M type: in skeletal muscle and liver

¤H4 isozyme (type 1): high affinity for lactate, lactatepyruvate,

under aerobic condition

H3M1 isozyme (type 2)

H2M2 isozyme (type 3)

H1M3 isozyme (type 4)

M4 isozyme (type 5): pyruvate  lactate

under anaerobic condition

 a series of homologous enzymes,

foster metabolic cooperation between organs.

slide20

Ex. 11

Biotin: abundant in some foods and is synthesized by intestinal bacteria

Avidin (Mr 70,000): rich in raw egg whites/a defense function

The Biotin-Avidin System can improve sensitivity because of

the potential for amplification due to multiple site binding.

Purification

slide21

96T2

96T3

97T

slide22

97T

98T

slide25

96C

97C