## Gluconeogenesis-Specific Enzymes **Key Point:** PEPCK (phosphoenolpyruvate carboxykinase) is the first committed enzyme unique to gluconeogenesis, catalyzing the conversion of oxaloacetate to phosphoenolpyruvate (PEP). ### The Four Gluconeogenic Bypass Enzymes Gluconeogenesis bypasses three irreversible glycolytic reactions using four unique enzymes: | Glycolytic Reaction | Gluconeogenic Enzyme | Substrate → Product | Location | | --- | --- | --- | --- | | Pyruvate → Acetyl-CoA | Pyruvate carboxylase | Pyruvate → Oxaloacetate | Mitochondria | | Oxaloacetate → PEP | **PEPCK** | Oxaloacetate → PEP | Mitochondria/Cytosol | | Fructose-1,6-bisphosphate → Fructose-6-phosphate | FBPase-1 | F-1,6-BP → F-6-P | Cytosol | | Glucose-6-phosphate → Glucose | Glucose-6-phosphatase | G-6-P → Glucose | ER | **High-Yield:** PEPCK is rate-limiting for gluconeogenesis and is induced by glucagon and cortisol; it is inhibited by insulin and AMP. ### Why PEPCK is Unique **Clinical Pearl:** PEPCK deficiency is rare but causes severe hypoglycemia and lactic acidosis because oxaloacetate accumulates and is shunted toward lactate production instead of glucose synthesis. **Mnemonic:** **"PEP-CK Makes PEP"** — PEPCK is the enzyme that makes phosphoenolpyruvate, the critical intermediate that bridges the mitochondrial and cytosolic phases of gluconeogenesis.
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