W5 Carbohydrate metabolism Flashcards
Hypoglycaemia
Muscle weakness Loss of coordination Mental confusion Sweating Hypoglycaemic coma and death
Hyperglycaemia
Non enzymatic modification of proteins
- Cataracts, - Lipoproteins important in atherosclerosis
Hyperosmolar coma
Glycogen
Large, heavily branched molecules which consist of alpha glucose molecules which are connected by alpha 1-4 (straight) and alpha 1-6 (on branched) glycosidic bonds
Need glycogenin for formation
Glycogen synthesis
G6P into G1P through phosphoglucomutase
G1P into UDP-glucose by UDP-glucose-pyrophosphorylase using UTP (more readily available for reactions)
Glycogenin reacts w/ UDP-glucose + catalyses addition of first glucose molecule. This then acts as substrate for glycogen synthase (PKA converts to b form)
Forms around 11 residues of glycogen then the glycogen branching enzyme adds branches to growing glycogen molecule
Why glycogen
Cannot store glucose as it is osmotically active
400mM glucose is stored as 0.01mM glycogen
Fat can not be mobilised as readily
Fat cannot be used as an energy source in the absence of oxygen
Fat cannot be converted in to glucose
Glycogen breakdown
Glycogen phosphorylase cleaves bond linking a terminal glucose residue to a glycogen branch by substitution of a phosphoryl group for the α[1→4] linkage
G1P into G6P by phosphoglucomutase
Glucose residues phosphorolysed from branches of glycogen until 4 residues before a glucose that is branched with a α[1→6] linkage
Glycogen debranching enzyme then transfers three of the remaining four glucose units to the end of another glycogen branch.
This exposes the α[1→6] branching point, which is hydrolysed by α[1→6] glucosidase, removing the final glucose residue of the branch as a molecule of glucose and eliminating the branch
The glucose is subsequently phosphorylated to glucose-6-phosphate by hexokinase
Phosphorylase removes G1P. G1P into G6P (PGM). G6P into glucose by G6phosphatase
Glycogen breakdown summary
Four enzymes required to breakdown glycogen five needed to form glucose
Phosphorylase breaks the alpha 1-4 links
Translocase
Debranching enzyme alpha 1-6
Phosphoglucomutase converts G1P to G6P
Glycogen phosphorylase
Key enzyme in glycogenolysis and its activity forms glucose-1-phosphate
Glycogen phosphorylase is a large, multi-subunit enzyme (highly expressed)
Many phosphorylase molecules are bound to each glycogen particle
G6P formed provides fuel for working muscles
In liver, G6P is de-phosphorylated (by glucose-6-phosphatase) and secreted into the blood, maintaining the 5 mmol/l blood sugar
Allosteric enzyme = has sites away from the active site that control its activity by inducing shape changes in the protein
Control of glycogen phosphorylase
Glycogen phosphorylase b (inactive) is converted to the active a form by a special enzyme – phosphorylase b kinase – which transfers a phosphate from an ATP to one serine residue on each phosphorylase subunit
Regulated by:
Ca2+
ATP
Phosphorylation
Hormonal regulation of glycogenolysis
Insulin inhibits
Glucagon stimulates in the liver
Adrenaline stimulates in muscle
Cortisol is a weak stimulus
Control of glycogen phosphorylase in muscle + liver
In muscle glycogen phosphorylase b can be activated by 5´-AMP (forms when aATP depleted) without being phosphorylated
ATP binds to the same site and blocks activation
G6P also blocks 5´-AMP activation
In the liver the activated phosphorylase a is inhibited by glucose
Activation of phosphorylase b kinase by Ca2+
Ca2+ ions activate phosphorylase b kinase
- In muscle, mediating glycogenolysis during muscle contraction
Only get max activity with Ca2+ and phosphorylation
- In liver α-adrenergic activation stimulates Ca2+ release
Reciprocal regulation of glycogen synthesis and degradation
Glycogen synthase = activated in times of plenty
Activated by ATP and G6P
Inactivation by phosphorylation (by protein kinase A)
Activated by dephosphorylation (by protein phosphatase-1
Glycogen phosphorylase = activated when glucose is in short supply
Inactivated by ATP and G6P
Activated by phosphorylation (by phosphorylase b kinase
Inactivated by dephosphorylation (by protein phosphatase-1
Pentose phosphate pathway
G6P → R5P (NADPH made, which converts GSSH into 2 GSH)
CO2 released
NADPH = for fatty acids, steriods etc from precurors + important for synthesis of molecules in cell that prevent distress
R5P (precursor) into nucleotides, coenzymes DNA, RNA
Gluconeogenesis
Body maintains blood glucose because it is the preferred fuel for the brain and the only fuel for RBC
Daily requirement = 160g, the brain needs 120g
Total body reserves = 210g
Gluconeogenic pathway converts pyruvate to glucose
Takes place mostly in the liver and a little in the kidney but during starvation kidney productions rises to 40%
Three most important substrates for gluconeogenesis are the amino acid (alanine), lactate and glycerol
