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Understanding Glucose Disposal: Glycogen Synthase and Phosphofructokinase in Cellular Energy Balance

Explore how glycogen synthase and phosphofructokinase regulate carbohydrate metabolism, insulin stimulation, and energy charge in cells. Learn about carbohydrate structures, isomers, glycosidic bonds, and sugar tests.

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Understanding Glucose Disposal: Glycogen Synthase and Phosphofructokinase in Cellular Energy Balance

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  1. Lecture 9 Glucose Disposal and Carbohydrate Structure

  2. Glycogen Synthase • Catalyses the addition of ‘activated’ glucose onto an existing glycogen molecule • UDP-glucose + glycogenn UDP + glycogenn+1 • Regulated by reversible phosphorylation (covalent modification) • Active when dephosphorylated, inactive when phosphorylated • Phosphorylation happens on a serine residue • Dephosphorylation catalysed by phosphatases (specifically protein phosphatase I) • Phosphorylation catalysed by kinases (specifically glycogen synthase kinase) • Insulin stimulates PPI • And so causes GS to be dephosphorylated and active • So insulin effectively stimulates GS

  3. Phosphofructokinase • Catalyses the second ‘energy investment’ stage of glycolysis • Fructose 6-phosphate + ATP  fructose 1,6 bisphosphate + ADP • Regulated allosterically • Simulated by concentration changes that reflect a low energy charge • An increase in ADP/AMP and a decrease in ATP • These molecules bind at a site away from the active site – the allosteric binding sites. • Many other molecules affect PFK allosterically but all are effectively indicators of ‘energy charge’

  4. Coupling (again!) • The stimulation of glycogen synthesis by insulin creates an ‘energy demand’ • Glycogenesis is anabolic • The activation of glucose prior to incorporation into glycogen requires ATP • This drops the cellular [ATP] and increases the [ADP] • This drop in ‘energy charge’ is reflected by a stimulation of PFK • A good example of how an anabolic pathway requires energy from a catabolic pathway • Insulin has ‘indirectly’ stimulated PFK and glucose oxidation even though it does not have any direct lines of communication to this enzyme

  5. Carb structure - general • - CHOH- with -C=O .... • makes it a good reducing agent (it, itself can be oxidised) • Aldoses and ketoses • -C=O in aldehyde or ketone position • simplest 3C trioses glyceraldehyde and dihydroxyacetone • no chiral centres in the latter, but one in the former (L & D) • Tetroses (4C) – another chiral carbon appears • Pentoses (5C) pentoses • Can also form ring structure (happens very fast)- -C=0 reacts with one of the far-away CHOHs • creates another stereo-centre • anomeric carbon - alpha or beta - (changing all the time in solution). • Hexoses (6C) - now four chiral centres 24=16 in the aldose • most commonly occurring in nature is the form that has all the -OHs in a plane – D-glucose • Can form a ring in solution – continually opening and closing • Chair and boat configuration

  6. More ‘chemistry’ • Stereoisomers • molecules with the same formula but different spatial arrangements • What you DON’T need to know • Enantiomers • Stereoisomers that are mirror images of each other • Diastereomers • Stereoisomers that are not mirror images • What you DO need to know… • Epimers - differ in orientation around just one carbon atom. • Glucose and mannose, glucose and galactose. • Anomers – differ in the carbon formed by the ring • Numbering of glucose. May seem pedantic but important when dealing with radioactivity! • Glycosidic Bonds between monosaccharides. • a1-4 and a1-6 glycogen, starch. • b1-4 cellulose • a1-2 sucrose, • b1-4 lactose • No longer reducing sugars when in these bonds. • Ring opening/closing no longer possible

  7. Nomenclature

  8. Ring Formation Attack of O on C5 to C1. O on C1 becomes new OH group

  9. Haworth Projections Pyranose ring Furanose ring

  10. Maltose Glycosidic bonds between 1 (alpha anomer) and 4… a14 Still a reducing end (glucose ring on the right can still open)

  11. Lactose Glycosidic bonds between 1 (beta anomer) and 4… b14

  12. Sucrose glucose fructose Glycosidic bonds between 1 (alpha anomer) and 2… a12

  13. Glycogen/Starch Glycosidic bonds between 1 (alpha anomer) and 4… a14 but also a16

  14. Cellulose Glycosidic bonds between 1 (beta anomer) and 4… b14 Enables lots of hydrogen bonds between chains and a lattice fibre structure

  15. Sugar Tests • Free anomeric carbon – a reducing sugar! • transient formation of the aldehyde in solution • Capable of reducing H2O2, ferricyanide, some metal ions (Cu2+, Ag+) • Fehling’s test (Cu) – red ppt • Tollen’s test (Ag) – silver mirror • Most usually done enzymatically and spectrophotometrically • Glucose oxidase – production of H2O2 • Colour changes or measured electrochemically • The aldehyde group also makes glucose quite dangerous to have in your body at high concentrations for long periods of time

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