catabolic core of metabolism

uniporter

glucose transporter family membrers glut 1-14

GLUT 1

ubiquitous expression

basal glucose uptake

GLUT 2

liver ,pancreas, brain, kidney, small intestine

high capacity, low affinity glucose transporter

glucose sensing role in islets

glut 3

• brain, placenta

• basal glucose uptake

glut 4

• muscle , fat , heart, hippocampal neurons

• insulin responsive glucose transpoter

symporters

• sodium glucose co transporters

SLGT1

• small intestine

• absorption of glucose from small intestine

SLGT 2

• kidney

• glucose resorption from glomerular ultrafiltration

glycolysis

1. glucose is phosphorylated upon entry into the cell by hexokinase to G6P and this stops glucose diffusing back across the transporter

2. G6P is isomerised to F-6-P and phosphorylated to form F-1,6-BP

3. this invests 2 molecules of ATP

4. one 6c molecule is lysed into 2 3C

5. the coenzyme NAD+ is reduced to NADH

6. 4 molecules of ATP produced- net 2

7. two mplecule sof pyruvate produced

glucose uptake

• facilitated diffusion across non insulin dependent glucose transporters

• insulin responsive tissues express GLUT 4 -hormonal control of glucose uptake

hexokinase

allosterically inhibited by glucose 6 phosphate

if pathway is slow and G6P conc rise, not wasting atp to phosphorylate glucose cannot be used yet

different tissue specific hexokianse have diff affinities for glucose enabling glycolysis to occur prefentially in extrahepatic tissue

phosphofructokinase

what does it do and what is it inhibited and activated by

• catalyses first step of glycolysis- the rate limiting step

• allosterically inhibited by atp, citrate and protons

• activated by AMP

pyruvate kinase

• alloserically activated by F-1,6BP

• allosterically inhibied by ATP and alanine

intermediates used by anabolic pathways to generate…

• nucelotides

• lipids

• amino acids

• other organic molecules

pyruvate dehydrogenase complex

• enzyme linking glycolysis to krebs cycle

• inhibited by high conc of atp, acetyl coA and NADH

citrate synthase

• atp is an allosteric negative regulator

• regulation important as oxaloacetate is utilised in gluconeogenesis in the liver

isocitrate dehydrogenase

ADP is a positive allosteric regulator

ATP and NADH are negative allosteric regulators

converts isocitrate to alpha ketoglutarate

alpha ketoglurate dehydrogenase complex- what is it inhibited by

• inhibited by high conc of its own products, NADH and succinyl coA and additional inhibtion by high atp levels

ETC creating a proton gradient

• COMPLEX 1- NADH from the krebs cycle donates 2 electrons to complex i.

• 4 hydrogen ions are pumped out matrix into intermembrane space

• COMPLEX II- FADH2 from the Krebs cycle is used in the conversion of succinate to fumarate by succinate dehydrogenase.

no direct pump of hydrogen ions

• COMPLEX III- coenzyme q transfers electrons to complex iii. complex iii shuttles two electrons from coenzyme q onto cytochrome c.

4 hydrogen ions are pumped out of the matric into the intermembrane space

• COMPLEX IV- accepts electrons from cytochrome c. (haem group in cytochrome c carries out electron transport)

electrons then shuttled through complex iv and onto oxygen producing water (oxygen = final electron acceptor

• COMPLEX V ATP SYNTHASE- i-iv used to establish proton gradient.

proton motive force drives ATP synthase

catalyses addition of phosphate groups onto ADP to ATP

ATP synthase structure

• multi protein complex embedded in the inner mitochondiral membrane that extends into the mitochondrial matrix

• central core of the complex turns due to rotational forces provided by the movement of hydrogen ions through channels in the membrane embedded portion

• beta subunits contain active site and catalyse ADP—→ ATP

• there are 3 beta subunits and so each full rotation of the central core results in synthesis of 3 ATP

the krebs cycle products for every turn of the cycle

• 2xCO2

• 3x NADH

• 1x FADH2

• 1x GTP

what are intermediates used by anabolic pathways to generate

• nucleotides

• lipids

• amino acids

• other organic molecules

what is the actual ATP yield

• 30

• NADH and other substrates from cytosol need to enter mitochondria- shuttle mechanisms result in a loss of mitchondria (-2ATP)

• Protons utilised in the transport of molecules across the inner membrane

• proton leak (uncontrolled backflow of protons through the inner mitochondrial membrane bypassing ATP synthase) can occur so yields about 2.5ATP per NADH and 1.5 ATP per FADH2

• proton gradient drives a pump not a fixed reaction (slippage- complex transport fewer protons than what is thermodynamically expected)

• so lower than calc

brown apidose tissue

• contain a large number of mitochondria

• enables endogenous heat production to maintain body temp independent of env temps

• important in newborns who cannot yet produce heat through shivering

• highly vascularised

• hibernators have a large amount of BAT due to need to rewarm from hypothermic torpor through hibernation

brown vs beige vs white

uncoupling the electron transport chain from ATP production

• allow protons to leak back into the mitochondrial matrix without passing through ATP synthase by creating alternative pathways

• this dissipates the proton gradient that normally powers ATP synthase releasing heat energy instead

• eg thermogenin (UCP1) is found in brown apidose tissue and is activated by norepinephrin and free fatty acids