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Glycolysis and Gluconeogenesis. 1. Energy –conversion pathway 2. Pathway tightly regulated 3. Synthesis of glucose from non-CH procusors 4. Glycolysis and Gluconeogenesis are reciprocally regulated. Glucose metabolism generates ATP -> powers muscle contraction.

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slide1

Glycolysis and Gluconeogenesis

1. Energy –conversion pathway

2. Pathway tightly regulated

3. Synthesis of glucose from non-CH procusors

4. Glycolysis and Gluconeogenesis are reciprocally regulated

Glucose metabolism generates ATP -> powers muscle contraction

slide2

Glucose is generated by Dietary Carbohydrates

Starch + glycogen: main source of glucose

Mainly brocken down by α-amylase (cleaves α 1->4)

slide5

Stage 1: Preparation of glucose by phosphorylation

-> Trapping of glucose in the cytosol

-> High-energy forms of glucose: destabilisation -> activation of glucose

Kinases: Phosphorylate substrates

-> Induced-fit mechanism of substrate recognition: closure of cleft

-> Shields active site from water

slide6

Stage 1: Preparation of glucose by phosphorylation

Phosphoglucose isomerase

-> Conversion of aldose into ketose -> preparation for addition of second phosphate group

-> isomerase: open hemiacetal -> isomerisation -> close hemiketal

slide7

Stage 1: Second phosphorylation

Phosphofructokinase -> control point of glycolysis

-> allosteric enzyme

slide8

Stage 2: Cleavage of C6 into 2x C3

Not directly used in glycolysis

directly used in glycolysis

Aldolase -> catalysis reverse aldol condensation

ketose

aldose

Isomers

Reaction driven in GAP direction by removal of product through glycolysis

slide9

Stage 2: Triose Phosphate Isomerase (TPI)

Triose phosphate isomerase (TPI)

  • -> Isomerisation accelerated 1010-fold
  • -> Kcat/Km = 2 108 M-1 s-1 -> kinetically perfect enzyme
  • -> suppresses an undesired side reaction

TPI traps enediol intermediate -> prevents side reaction -> opens again when GAP formed

Reaction 100 times faster

stage 3 oxidation of c3 and atp production pay off phase
Stage 3: Oxidation of C3 and ATP production -> Pay Off Phase

2 steps in one reaction:

ΔG°´= -50 kJ mol-1

ΔG°´= +50 kJ mol-1

  • Reaction -> thermodynamically favorable
  • Reaction -> not favorable
stage 3 mechanism of gap dehydrogenase
Stage 3: Mechanism of GAP dehydrogenase

Transfer of a hydride ion (H-) to NAD+

Formation of thioester intermediate makes 2nd reaction (phosphorylation) possible !!

Attack of the thioester by orthophosphate ion

slide12

Stage 3: Formation of ATP

Formation of ATP in this manner -> Substrate-level phosphorylation

Rearrangement of phosphoryl group

Irreversible reaction -> ATP is profit!!!!!

Dehydration: formation of enol phosphate

Higher phosphoryl-transfer potential (Phosphoryl group traps molecule in unstable enol form)

slide13

Summary of glycolysis

-> 10 reaction steps

-> 1 x C-6 (glucose) converted into 2x C-3 (pyruvate)

-> oxidation of glucose -> 2 NADH generated

-> 2 ATPs used + 4 ATPs generated -> pay off: 2 ATPs

slide14

Glucose Metabolism Under Aerobic and Anaerobic Conditions

Final Electron-acceptor:

Aerobic -> O2

Anaerobic -> Pyruvate

Cytosol

slide15

Why do we need to produce lactate or ethanol (yeast) anaerobic and not stop at pyruvate?

-> Regeneration of NAD+

Gycolysis: Oxidation reaction generates NADH from NAD+

Under anaerobic conditions: reaction from Pyruvate to Lactate or Ethanol -> regenerate NAD+

Under aerobic conditions: regeneration of NAD+ happens in respiratory chain (mitochondria) -> via 2 different shuttles

slide16

Entry points for other sugars into glycolysis

Uridine diphosphate galactose

Galactose toxic if transferase is missing

slide17

Glycolysis is tightly regulated

  • 2 major metabolic needs: ATP and Pyruvate (Acetyl-CoA)
  • Enzymes catalysing irreversible reactions: sites of control (allostery)
  • Hexokinase, phosphofructokinase, pyruvate kinase
  • Allosteric control (ms), phosphorylation (s), transcriptional regulation (h)

Phosphofructokinase: the key enzyme in glycolysis control

  • Inhibited by ATP (reversed by AMP)
  • Inhibited by low pH
  • Inhibited by citrate (Citric acid cycle)
slide18

Regulation of glycolysis in the muscle

-> ATP based regulation

ATP inhibits all 3 enzymes

Need for ATP (high AMP) activates PFK

slide19

Regulation of glycolysis in the liver

Regulation by: -> ATP

-> glucose level in blood

-> need for building bocks for biosynthesis

slide20

Regulation of glycolysis in the liver

Proteins responsible for uptake of glucose into the cell -> regulate blood glucose level

Uptake of glucose (tranporters) -> metabolism of glucose

cancer and exercise affect glycolysis in a similar way
Cancer and exercise affect glycolysis in a similar way

Tumors -> enhanced uptake of glucose -> enhanced glycolysis

Hypoxia: O2 deficiency

Tumor cells grow too fast -> not enough O2 for aerobic process -> unaerobic conditions (lactate)-> glycolysis primary source for ATP production

-> induction of blood vessel growth

slide23

Synthesis of glucose from non-carbohydrate precursors:

-> gluconeogenesis

  • Brain and blood cells depend on glucose -> 160g/day (mainly for the brain)
  • Glucose in the blood: 20g, as glycogen: 190g
  • Starvation > 1day  other metabolites for energy!
  • -> Gluconeogenesis pathway:
  • Takes place in liver (and kidneys)
  • Important to maintain blood glucose level
  • Major precursors: glycerol, amino acids, lactic acid
  • Specific enzymes in addition to glycolysis
  • (for the irreversible steps in glycosis)
slide24

Synthesis of glucose from non-carbohydrate precursors:

-> gluconeogenesis

Triacylglycerols (Lipids) taken up by diet

-> brocken down to fatty acids and glycerol

cannot by converted to glucose

glucose

slide25

Glycolysis <-> gluconeogenesis

Gluconeogenesis is not the reversal of glycolysis !!!

Glycolysis: in the cytosol

Gluconeogenesis: major part in cytosol

-> 1st step in mitochondria -> shuttle

Biotin: prosthetic group -> carrier for CO2

Reverse reaction of glycolysis thermodynamically not favorable !!!

slide26

Synthesis of glucose from non-carbohydrate precursors:

-> gluconeogenesis

Pyruvate (end product of glycolysis) -> under aerobic conditions -> shuttle into Mitochondria -> converted into acetyl-CoA -> citric acid cycle

Gluconeogenesis -> start with pyruvate in mitochondria

1st Step: convertion to oxaloacetate

-> malate/oxaloacetate shuttle

glycolysis

slide27

Synthesis of glucose from non-carbohydrate precursors:

-> gluconeogenesis

Free glucose is important control point -> pathway ends mostly with glucose-6-P

-> finished just if glucose is needed (in blood)

-> advantage of stopping at glucose-6-P

-> trapped in the cell (cannot shuttle outside)

Last step of gluconeogenesis: in ER lumen

-> glucose shuttled back to cytosol -> leaves cell

slide30

Reciprocal regulation of glycolysis & gluconeogenesis

  • Pathways not active at same time
  • Regulated by products of reaction and precursors (allostery)
  • Regulated by hormones: glucagon & insulin, through F-2,6-BP
  • Regulated at the transcriptional level of genes

glucagon

insulin

transcription

In the liver: aim is to maintain blood glucose level

slide31

Balance between glycolysis and gluconeogenesis in the liver

-> sensitive to blood glucose concentration

Regulated by a bifunctional enzyme: PFK2/FBPase2

-> formed by PFK2

-> hydrolysed (dephosphorylated) by FBPase2

-

Fructose bisphophatase 2

Phosphofructokinase 2

slide32

Balance between glycolysis and gluconeogenesis in the liver

-> sensitive to blood glucose concentration

High blood-glucose level -> insulin-> high level of F-2,6-BP

Low blood-glucose level -> glucagon-> low level of F-2,6-BP