Metabolic Pathways and Glycogen Turnover

Pentose Phosphate Pathway

The pentose phosphate pathway is an alternative route for glucose catabolism, accounting for 5-50% of glucose breakdown, typically less than 10%. It plays a significant role in cells undergoing:

  • Active cell division, such as tumor cells.

  • Active fatty acid synthesis, like adipose tissue.

The pathway involves:

  • Glucose-6-phosphate (G6P) dehydrogenase.

  • 6-phosphogluconate dehydrogenase.

Key conversions:

  • G6P to 6-phosphogluconate.

  • 6-phosphogluconate to Ribulose-5-phosphate.

  • Ribulose-5-phosphate to Ribose.

The pathway generates NADPH from NADP+ and produces ribose sugars.

Specific Functions and Regulation of Pentose Phosphate Pathway

Functions:

  • NADPH Production: Essential for biosynthetic pathways like fatty acid and sterol synthesis.

  • Ribose Sugar Production: Necessary for nucleotide synthesis, supporting RNA and DNA creation.

Regulation:

  • Enzyme Quantity: The amount of G6PDH and 6PGDH protein is reduced during starvation.

  • Transcriptional Control: Insulin activates transcription of both G6PDH and 6PGDH genes via SREBP-1c, while glucagon inhibits transcription through CREB.

Glycogen Turnover: Synthesis of Glycogen

Glycogen synthesis involves:

  • Glycogenin: Functions as a primer. Exists in two isoforms (1 or 2) with molecular weights of 37 or 66 kDa.

  • Autocatalysis: Glycogenin adds glucose to a single tyrosine residue.

  • Glycogen Synthase (GS)

  • Branching Enzyme (BE)

Process:

  1. Glycogenin adds the first glucose molecule from UDP-glucose.

  2. Glycogenin extends the chain to 6-8 glucose units.

  3. Glycogen synthase and branching enzyme extend the glycogen molecule further.

  • GYG1 is the "muscle" isoform of glycogenin.

  • GYG2 is the "liver" isoform of glycogenin.

Glycogen Turnover: Breakdown of Glycogen

Glycogen breakdown leads to Glucose-6-Phosphate, which can then enter:

  • Glycolysis

  • Other metabolic pathways.

Key enzymes involved:

  • Glycogen Phosphorylase: Breaks down glycogen into Glucose-1-Phosphate using inorganic phosphate (Pi).

  • Debranching Enzyme: Removes branches in glycogen.

  • Phosphoglucomutase: Converts Glucose-1-P to Glucose-6-P.

Also:

Glucose-6P \rightleftharpoons Glucose-1-P + UTP \rightleftharpoons UDP-glucose + PPi

Structural Features of Glycogen

Glycogen is a branched, complex molecule with:

  • Spherical shape, visible with a diameter of approximately 30nm.

  • Contains around 60,000 glucose units.

  • Exists as β particles, which associate to form α particles in the liver (20-30 β particles).

Significant Complex includes:

  • Potential backbone protein.

  • Enzymes for synthesis and breakdown.

  • Regulatory protein kinases and phosphatases (PP-1G).

  • Cytoskeleton interactions.

Glycogen storage diseases (e.g., involving GYG1) are also relevant.

Glycogen: Storage Sites and Amounts

  • Most cells store some glycogen as a short-term fuel reserve.

  • Muscle tissue stores around 200g, a significant reserve.

  • The liver stores about 70g, primarily for release and use by other tissues during starvation. The regulation differs between liver and other tissues.

Glycogen Synthase (GS) Regulation

  • GS is an 81kDa monomer, functional as a homodimer.

  • GS1 is found in muscle and other tissues.

  • GS2 is a version for liver.

Regulation:

  • Active Form: GSa

  • Inactive Form: GSb

Conversion:

  • Protein phosphatase 1G activates GSa by dephosphorylation.

  • Protein kinases inactivate GSa by phosphorylation such as Protein kinase A, AMPK, GSK3, and Ca-dependent kinases.

Insulin and G6P also influence GS activity favoring the active form.

Glycogen Phosphorylase (GP) Regulation

  • GP is a 100kDa homodimer, exists as 3 gene products (“liver”, “brain”, “muscle”).

Regulation:

  • Active Form: GPa

  • Inactive Form: GPb

Conversion:

  • Protein phosphatase 1G activates GPb by dephosphorylation.

  • Glycogen phosphorylase kinase activates GPb by phosphorylation.

Other Regulatory Factors:

  • G6P allosterically inhibits.

  • AMP allosterically activates.

  • Phosphorylation mainly regulates liver GP activity.

Glycogen Phosphorylase Kinase (GPK) Regulation

  • Active Form: GPKa

  • Inactive Form: GPKb

Conversion:

  • Protein phosphatase 1G dephosphorylates GPKa to GPKb.

  • Protein kinases (cAMP, Ca2+) phosphorylate GPKb to GPKa.

GPb phosphorylation is regulated by GPK activity.

Summary of Glycogen Turnover Regulation

  • Glycogen synthesis involves the conversion of Glycogen(n residues) to Glycogen(n+1 residues) via GSa.

  • Glycogen breakdown involves the reverse via GPa.

  • GS and GP are reciprocally regulated by phosphorylation and dephosphorylation.

  • Protein kinases phosphorylate and inactivate GSa and activate GPb.

  • Protein phosphatase 1G dephosphorylates and activates GSa and inactivates GPb.

  • Insulin and G6P promote glycogen synthesis by affecting the activity of GS and GP.

Complexity of Glycogen Regulation

Insulin signaling leads to rapid changes in GP and GS activity.

Handling Other Sugars

  • Sucrose: Digestion yields Fructose + Glucose.

  • Fructose:

    • In the liver, fructokinase converts fructose to Fructose-1-P.

  • Lactose: Digestion yields Galactose + Glucose.

  • Galactose:

    • In the liver, galactokinase processes galactose.

Integration of Metabolism

Basic metabolic features are shared by cells, but metabolic function and regulation differ between tissues.