lecture 10 - glycolysis

• We eat so we can grow, so we can survive, so we can move, we can reproduce but if we really look down into the sort of basics of this thing we’re trying to do is maintain integrity • We need to keep our cells constantly turning over, we’ve got damage to membranes. Ther eis damage coming from reactive oxygen species from the environment • So we’ve really got to try and maintain homeostasis, keep our cells alive, stop them leaking everywhere, protect against damage

• What we eat is a combination of things, its carbohydrates, proteins, fats etc… • So there is quite a complex mixture that we’ve got to then try and break down into its constituents to then be able to absorb the energy to carry out this cell homeostasis All of these components provide the fuel for cellular respiration, and its cellular respiration

• well this feeds into numerous pathways, one of them that we look at is, carbohydrates feeding into glycolysis which is that top panel up there • But also we can feed into pyruvate directly and also into this compound call acetyl coenzyme A, which then feeds into the citric acid cycle

-proteins = amino acids -carbohydrates = fructose, glucose and galactose -fats/lipids = fatty acids and glycerol

citric acid cycle

Glycolysis is where we take sugars such as glucose, we generate some energy in the form of ATP and reducing equivalence to the form of NADH, to generate pyruvate

we take the pyruvate and generate acetyl coA together with some NADH and that feeds into the krebs cycle where we generate ATP

we take some of these reducing equivalencies NADH’s and FADH2’s and then we drive ATP generation using this chemiosmotic theory

• three main depots where this occurs, so we could be considering adipose tissue, where we can push lipolysis which allows us to break down the fatty acids and glycerol and those can feed into the pyruvate and acetyl coenzyme A pools • We can take the sugars into the liver and we can generate pyruvate • And we can take amino acids into the muscle again to generate pyruvate and drive the citric acid cycle

• So hopefully you have maybe had some lipids, some glucose, some amino acids, and they are in your guts, they are going to pass through into your bloodstream and the fats, first of all, are going to go to your liver where they are going to get processed and they are going to end up being packaged and transported to adipose tissue and some of that will then get released to the muscle to allow you to concentrate on things like this lecture • The glucose is going to be transported to multiple organs, the liver, the brain, the muscle, adipose • The brain always exclusively uses glucose as an energy source, it is really important that that’s provided and the amino acids will go to the muscle where it is used as an energy source • But obviously after the fed state we want to store some of that energy, we want to be able to keep it for later, it is all well and good being able to use it in the here and now but if we don’t know when we are going to have our next meal, we need to be able to make some stores and one way to be able to store energy is in the form of glycogen

-highly branched -1,4 and 1,6 glycosidic bonds -stored as granules in the cytosol of the cell -high conc in the liver, this is releasable in to the circulation -high amounts in muscle, for local use only during exercise/fasting

The muscle does not have an enzyme to breakdown a form of glucose, the enzyme glucose-6-phosphotase would allow the glucose to go into the circulation

• So what happens is you start releasing fatty acids from the adipose tissue and we will look in the second lecture about how much energy you get out of these free fatty acids • But they get released to the liver and they get released to the muscle where they can be used to generate energy • Glucose then gets released from glycogen, and that is used by the brain or as I said the brain needs the glucose as an energy source, so the liver can readily provide high levels of glucose • And the glycogen can be used within the muscle to be broken down and used as a local energy source within the muscle itself

• You have got to then start releasing many, many more amounts of free fatty acid out from the adipose tissue, releasing this free fatty acid to the liver, you are going to then have to ramp up your glucose release from the liver for glycogen • But if you have not got enough, you now need to start actually synthesising glucose • You need to do this thing called gluconeogenesis which is where you take down what were the breakdown products of glucose and you start to build glucose molecules from those metabolites • But also you will start generating amino acids and lactate within your muscle But amino acids again, breakdowns of protein, you start having to use them as an energy source, you don’t necessarily really want to because proteins are obviously really good at being able to maintain your ell integrity and for transporting things and metabolising other things and being enzymes but you need to release the amino acids from those proteins to give the energy supply so your brain can maintain that high level of glucose that it needs

yes

28-32

2x pyruvate net 2 ATP molecules 2x NADH

-where you add an amine to the pyruvate and this allows you to synthesise L-alanine -so then the amino acid can go off to be involved in protein synthesis or you can use it to store energy and later on convert it to pyruvate

• The investment phase uses ATP • So we have got to use ATP to start off with to generate some high energy molecules which will then give us a payoff later on Because the pay off phase, gains more ATP back, you put two ATP in, you get 4 ATP back and you get 2 NADH out of it as well

• The trap, is where we add a phosphate to glucose, that is one of the first high energy things we need to do and that gives the glucose the energy to then be able to do the steps that are further down the line • The split = splitting the glucose, we need to split the glucose into those 2 3 carbon units The pyruvate maker = so actually taking the molecule phosphoenol-pyruvate and generating the pyruvate

• By facilitated diffusion • GLUT4 sits on the membrane of the muscle and allows glucose to enter, glucose then gets acted on by an enzyme called hexokinase, generates this phosphorylated glucose which can then either be used for glycogen synthesis or can go into glycolysis • That protein allows that facilitated diffusion to get that GLUT4 into the muscle

-glucose to glucose-6-phosphate using hexokinase -fructose-6-phosphate to fructose-1,6-biphosphate using phosphofructokinase -phosphoenolpyruvate to pyruvate using pyruvate kinase

• What we have to do to generate the glucose back, is we have to replace these irreversible steps with some alternatives • So the first one is this pyruvate kinase and each of these steps are called a bypass • So we have bypass number one, and what that does is it takes pyruvate and it generates oxaloacetate and then phosphoenolpyruvate and this uses one molecule of ATP and one molecule of GTP for every pyruvate we use • Fructose 1,6-biphosphate goes to fructose 6-phosphate • And ten for the hexokinase we can use a phosphatase, just trims the phosphate off • But what it doesn’t do is the reverse reaction of the fructose 6 phosphate and the conversion of glucose, you can see there we’ve used ATP in the glycolysis reaction but the reverse of it, the gluconeogenesis reaction does not allow us to generate ATP • We only release a phosphate but that is it • So overall the reverse reaction gives us 4 ATP, two GTP, 2 NADH for every glucose synthesised • So actually it is more expensive metabolically than glycolysis • So actually having to start for energy to make the glucose, we have to get that energy from somewhere else and typically it comes from things like fats that are released from the adipose tissue

oxygen