Week 2

Anaerobic Glycolysis Process: The intermediate reactions in anaerobic glycolysis begin with the cleavage of fructose 1,6-bisphosphate (Frc-1,6-bisP) into two triose phosphates: dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (Gl-3-P).
Conversion of Frc-1,6-bisP: This reaction is catalyzed by aldolase (reaction #8), which is a zinc-containing enzyme. This step represents the only degradation involving a carbon-carbon (C-C) bond in the Embden-Meyerhof Pathway (EMP).
Interconversion of Intermediates: DHAP and Gl-3-P can be converted to each other by triosephosphate isomerase (reaction #9). The equilibrium favors Gl-3-P formation due to its continuous phosphorylation to 1,3-bisphosphoglycerate (1,3-bisPG; reaction #15).

Fructose 1-Phosphate: Fructose 1-phosphate (Frc-1-P), which may arise from dietary fructose or through the Polyol Pathway, can also be cleaved into glyceraldehyde and DHAP by aldolase (reaction #10).
Access via Triokinase: Glyceraldehyde can enter the EMP through triokinase (reaction #11) which phosphorylates glyceraldehyde to glyceraldehyde 3-phosphate.

Requirement for NAD+: NAD+ is essential for glycolysis to proceed, particularly during the conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate.
ATP Production Site: The first site of ATP production in the EMP occurs during the conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate.
Fluoride Effect: Inhibition of the conversion of 2-phosphoglycerate to phosphoenolpyruvate with fluoride prevents changes in plasma glucose concentration in stored blood.
Irreversibility: The conversion from phosphoenolpyruvate to pyruvate is considered physiologically irreversible.
Diphosphoglyceromutase Role: This enzyme is responsible for forming an important glycolytic intermediate in erythrocytes.
ATP Yield in Anaerobic Glycolysis: The anaerobic phase yields less ATP than the aerobic phase.

Cleavage of Frc-1,6-bisP: Initial step produces DHAP and Gl-3-P.
Glyceraldehyde Conversion: Acting on glyceraldehyde include reactions by:
- Glyceraldehyde dehydrogenase (#12) leading to glycerate.
- Glycerate kinase (#13) catalyzing formation of 3-phosphoglycerate from glycerate.
Pathway to Glycerol: DHAP serves as a precursor to glycerol 3-phosphate, important in adipose tissue, catalyzed by glycerol 3-P dehydrogenase (#14).
Glycerol 3-Phosphate Shuttle: DHAP and glycerol 3-P participate in the glycerol 3-P shuttle, allowing electron transport across mitochondrial membranes without transferring NADH directly.

Necessity for Continued Glycolysis: NAD+ must continually be regenerated for glycolysis; this occurs via several pathways:
- Coupling with pyruvate conversion to lactate.
- Linking to DHAP to glycerol 3-P (#14).
- Via oxaloacetate to malate reactions.
Formation of 1,3-bisPG:
- Oxidation of Gl-3-P to 1,3-bisPG (
  $ext{Gl-3-P} <br>ightarrow ext{1,3-bisPG}$ ) catalyzed by Gl-3-P dehydrogenase (#15) utilizes inorganic phosphate (Pi) rather than ATP, producing NADH.

Phosphoglycerate Kinase Reaction:
$ext{1,3-bisPG} + ext{ADP} <br>ightarrow ext{3-PG} + ext{ATP}$ (reaction #16) results in the first ATP generation in the EMP from substrate-level phosphorylation, yielding 2 ATPs.
Energy Capture in Anaerobic Glycolysis: Overall conversion gives a net 2 ATP per glucose molecule, accounting for ATP usage in hexokinase and PFK reactions.

Aldolase: Catalyzes the cleavage of fructose 1,6-bisP.
Triosephosphate Isomerase: Facilitates the interconversion between DHAP and Gl-3-P.
Glyceraldehyde Dehydrogenase and Glycerate Kinase: Involved in the conversion processes leading to ATP production.
Phosphoglycerate Kinase: Critical for ATP synthesis via substrate-level phosphorylation.
Enolase: Catalyzes the dehydration reaction leading to phosphoenolpyruvate (
$ext{2-PG} <br>ightarrow ext{PEP}$ ).
Pyruvate Kinase: Finalizes the glycolysis process by converting PEP to pyruvate and generating ATP (reaction #21).

Liver vs. Muscle: Liver pyruvate kinase is activated by Frc-1,6-bisP but inhibited by alanine and ATP. Muscle pyruvate kinase is activated by low ATP/ADP ratios but not Frc-1,6-bisP, reflecting differing needs between the two tissues for gluconeogenesis.

Anaerobic vs. Aerobic Glycolysis:
- Anaerobic glycolysis yields 2 ATP per glucose molecule.
- Aerobic glycolysis may yield up to 38 ATP equivalents:
- 6 ATP from NADH produced (3 from each NADH entering the mitochondrial respiratory chain).
- 2 ATP directly generated in glycolysis.
Final Energy Metrics: Approximately 42% of the energy from glucose is captured through aerobic combustion, while the remainder dissipates as heat.

Outline all steps between Frc-1,6-bisP to pyruvate including intermediates and enzymes.
Explain glycolysis's dynamic relationship with the glycerol 3-P shuttle.
Recognize high glycerol kinase activity in liver and its uses in adipose tissue.
Understand the critical nature of NAD+ supply in anaerobic glycolysis and the reactions providing it.
Explain the roles of aldolase and triosephosphate isomerase in the EMP.
Identify and articulate the Rapoport Shunt's significance.
Discuss the practical reasons for fluoride's use in blood collection.
Analyze the regulatory differences in pyruvate kinase between liver and muscle.
Compare ATP yield from anaerobic versus aerobic glycolysis.
Identify and explain the irreversible reactions in glycolysis and their implications in gluconeogenesis.

Which enzyme catalyzes the only degradative step involving a C-C bond in EMP? (a: Aldolase)
Which reaction utilizes inorganic phosphate (Pi) instead of ATP? (e: Glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate)
The first ATP-generating reaction occurs during the conversion of which compound? (b: 1,3-Bisphosphoglycerate to 3-Phosphoglycerate)
Identify the glycolytic hexose intermediate: (b: Fructose 1,6-bisphosphate)
Name the two enzymes that facilitate substrate-level phosphorylation in EMP (c: Pyruvate kinase and Phosphoglycerate kinase).