Carbohydrate metabolism Flashcards
carb storage and utilisation
what is short term store of carbs? long term?
where is glycogen synthesis primarily important? (2) why?
how else can we make glucose? what is this process called? where does it take place? (2)
what pathway is important for making nucleotides and NADPH?
Carbohydates are stored as glycogen which acts as a short term energy store. Fats are a more long term storage device.
• Glycogen synthesis is primarily important in the liver and the muscle.
o Liver maintains glucose levels whilst muscles are the net user of glucose
- We can also make glucose for maintaining the circulating levels of glucose from non-carb sources, this is gluconeogenesis which takes place in the liver and kidney when needed
- Pentose-phosphate pathway is important for producing nucleotides and NADPH
The body aims to maintain blood glucose - hypoglycaemia and hyperglycaemia
normally what level?
what is critical low level?
symptoms?
why is hyperglycaemia bad too? what further issues can this lead to?
Normally 4-5mM, our critical blood glucose is 2.5mM – level below which prolonged life cannot be maintained = hypoglycaemia
Hypoglycaemia symptoms include: • Muscle weakness • Loss of coordination • Mental confusion • Sweating • Hypoglycaemic coma • Death.
Hyperglycaemia is also very dangerous as glucose is very reactive and at high concentrations it starts to modify proteins (non-enzymatically), causing them to not function properly. This can may lead to cataracts or modify lipoproteins important in atherosclerosis.
It can also lead to a hyperosmolar coma.
body is good at maintaining blood glucose over a range of activities
why is this the case? (2)
what may vary more?
Our body is good at maintaining blood glucose over a range of activities -> rest, exercise, blood glucose stays relatively same level.
This is because brain cells use glucose and RBC’s only use glucose. Fats are regulated more loosely so may vary much more.
How the body deals with excess and lack of glucose
excess (2)
lack (2)
• Excess blood glucose:
o Glycogen synthesis
o Pentose phosphate pathway (fatty acid synthesis)
• Lack of blood glucose:
o Glycogen breakdown
o Gluconeogenesis
G6P is a key intermediate molecule
if lack of atp?
if not lack?
If there is a need for energy it will go down the glycolytic pathway but if not, there are other routes
Glycogenesis
where? when? why? what regulates this?
where?
liver (100g) and muscle (300 - 400g)
when?
when blood glucose levels are high
Why?
glycogen is safe glucose store
what regulates this?
insulin
what is glycogen?
what type of glucose?
what type of link? where is the other links?
what acts as a primer? what does it allow?
if glycogen storage disease, what can it lead to?
Glycogen is a branched polymer of D-glucose, the majority of it is alpha 1-4 linked, but there are branches off it which are alpha 1-6 linked. = HIGHLY BRANCHED
An important part of glycogen is the protein glycogenin which acts as a primer, it allows the initiation of synthesis of glycogen. Therefore without it glycogen will not form.
Some people have glycogen storage diseases -> tend to suffer from muscular/neurological disorders
Glycogen Synthesis
what are the 2 key steps? what does G6P convert to via what? what does this react with to from with? what does this react with?
what enzyme is needed to increase chain length?
There are two key steps to glycogen synthesis:
• G6P is converted to Glucose 1 phosphate catalysed by phosphoglucomutase enzyme.
• G1P then reacts with UTP which activates the glucose molecule. This gives UDP-Glucose.
UDP-Glucose then reacts with (and binds to) glycogenin, this then allows glycogen synthase to add on UDP-Glucose to increase chain length.
Glycogen is a branched molecule
why branched?
how is this done? what does the brnahcinf enzyme and when? what links is formed?
what 2 process is going on when making glycogen?
hence which enzymes make which links?
Glycogen is a branched molecule and the reason for this is to give it lots of ends so that glucose can be mobilised from glycogen quicker.
The way this is done is that when the chain has 11 monomers of the glucose, some of that chain is removed and made into a branch. The enzyme that does this is branching enzyme.
This forms the alpha 1-6 links.
So ultimately you have two processes going on, the glycogen synthase adding individual units of glucose and the branching enzyme which allows formation of the branches
Glycogen synthase is the enzyme that forms the α1-4 glycosidic bonds
Branching enzyme forms the α1-6 branch points
Why Glycogen?
why good store? (2)
why not fat? (2)
• The reason why we have glycogen is because we cannot store glucose as it is osmotically active – i.e. would draw water into cells.
- Glycogen is much denser in that we can store 400mM glucose as 0.01micromolar of glycogen.
- Fat can also not be mobilised as readily, glycogen is quickly mobilised
- Fats also cannot be used as an energy source in the absence of O2, glucose can
- Fats cannot be converted to glucose
Glycogen Breakdown
Glycogenolysis
what is broken down first? what links are broken and via what enzyme? what will this give and what are these converted into? via what?
fate of G6P in muscle? why can’t it be used to control blood glucose in muscle? where can this be controlled? via what?
when does glycogen breakdown stop happening on the chain? what length? where does it go and via what?
what happens to the final residue left on the branch? via what enzyme? what does it form? where can it be converted into glucose?
what 4 enzymes are reqired?
where is G6P able to convert into glucose? (2) via what?
The way glycogen is broken down is in essence the reverse of synthesis. The enzyme important for breaking down glycogen will remove individual units until it eventually removes the whole branch.
The alpha 1-4 links are broken to remove the units individually, this is done by the enzyme phosphorylase.
• This will give glucose-1-phosphate, these are then converted to glucose-6 phosphate by the enzyme phosphoglucomutase.
The fate of this G6P will vary depending on the tissue, in muscle it can then be used for ATP synthesis for its own use. Muscle cannot use this to control blood glucose as it doesn’t contain the enzyme to convert G6P to glucose.
The liver does contain this enzyme (Glucose-6-phosphatase) and so is able to control circulating blood glucose.
So, going back to glycogen breakdown, the residues are removed till you get to a certain length left (an end portion of a particular branch), this portion left then gets broken off and moved onto the end of the main chain. This is done by the enzyme transferase. (3 units moved)
There is then a debranching enzyme which removes the final residue left on the branch, it removes it to form G6P which can be converted to glucose (in liver).
So as the entire process, four enzymes are required to breakdown glycogen (five are needed to form):
- Phosphorylase breaks the alpha 1-4 links (gives glucose 1-phosphate)
- Transferase moves end portion of branch to main chain/adjacent chain (3 units moved)
- Debranching enzyme removes alpha 1-6 link, removing the final residue on the branch (gives glucose)
- Phosphoglucomutase converts G1P to G6P
Glucose-6-phosphatase converts G6P to glucose present in liver and kidney but not muscle.
Glycogenolysis - stimulated by? (4)
occurs where? (2)
Stimulated by: glucagon, adrenalin, noradrenalin and Growth hormone
occurs in liver and muscle
Glycogen Phosphorylase
what is it a key enzyme for? what does its activity form?
what does the G6P allow for in muscles? what happens in liver?
what is glycogen phosphorylase an example of?
- Glycogen phosphorylase is a key enzyme in glycogenolysis and its activity forms glucose-1-phosphate.
- It is a large multi-subunit enzyme.
- Many phosphorylase molecules are bound to each glycogen particle.
- The G6P ultimately formed provides fuel for working muscles and in the liver G6P is dephosphorylated (by glucose-6-phosphatase) and secreted into the blood maintaining the 5mmol/l blood sugar.
Glycogen phosphorylase is an example of an “allosteric” enzyme, it is activated by phosphorylation but modulated by other factors.
Also regulated by reversible phosphorylation regulated by hormones such as insulin, glucagon, adrenalin and noradrenalin
Regulation of glycogen phosphorylase differs in muscle and liver
control of glycogen phosphorylase
what is the inactive form? what is it converted into? via what?
what activates phosphorylase? what binds to what receptor? what cascade is set off?
what does PKA activate? effect of this?
what else for PKA convert? why is this significant?
what is the hormonal regulation of glycogenolysis? (4)
Glycogen phosphorylase b (inactive) is converted to the active form -> phosphorylase a by a special enzyme phosphorylase b kinase.
• It can be further regulated by a number of different molecules related to the energy provision binding to allosteric sites, as well as the covalent phosphorylation mentioned.
Activation of Phosphorylase occurs through a cAMP cascade started ultimately by NA/A binding to a GPCR, the beta-adrenergic receptor, coupled to Gs, hence adenylate cyclase enzyme.
- This ultimately leads to synthesis of cAMP which activates protein kinase A (PKA).
- PKA then activates phosphorylase kinase (by phosphorylating it)
- Which can then convert phosphorylase b to phosphorylase a by phosphorylating phosphorylase b.
- Phosphorylase a is then able to cleave G1P from glycogen.
PKA also converts glycogen synthase a to glycogen synthase b -> by phosphorylating glycogen synthase a, which is inactive form which will mean synthesis of glycogen is inactivated so synthesis and breakdown are not occurring at the same time.
There is also hormonal regulation of glycogenolysis: • Insulin inhibits • Glucagon stimulates in liver • Adrenaline stimulates in muscle • Cortisol is a weak stimulus
control of glycogen phosphorylase
In muscle and liver
in muscle, what can activate phosphorylase b? when does this occur? what is this an example of?
what two things can block this activation? why?
in the liver, what inhibits the activated phosphorylase a? why does this occur?
In muscle, glycogen phosphorylase b can be activated by 5’-AMP, which forms when ATP is depleted, tells cell energy is needed, without being phosphorylated.
-> This is a form of allosteric regulation.
ATP binds to the same site and blocks activation (because energetic state for cell is high and requirement for glucose is low), G6P also blocks 5’-AMP activation, this is because there is enough energy in the cell already and more glucose isn’t needed.
In the liver the activated phosphorylase a is inhibited by glucose i.e. Glycogen breakdown by phosphorylase a is inhibited in the presence of glucose despite the enzyme being in the active form ‘a’. This is because glucose is meant to be released into circulation from liver therefore if glucose level is increased, need for glycogen breakdown is decreased.
