fructose-1,6-bisphosphatase

**Function and location** - Gluconeogenic enzyme that catalyzes: fructose-1,6-bisphosphate + H2O → fructose-6-phosphate + Pi. This is irreversible and bypasses the PFK-1 step of glycolysis. - Found in the cytosol of the liver, kidney cortex, and (to a lesser extent) intestinal epithelium. It is also present in muscle, where it has a regulatory role. - Gluconeogenesis bypasses 3 irreversible glycolytic steps. The enzymes are remembered as "Pathway Produces Fresh Glucose": - Pyruvate carboxylase (mitochondria) and PEP carboxykinase (cytosol) bypass pyruvate kinase. - Fructose-1,6-bisphosphatase bypasses PFK-1. - Glucose-6-phosphatase (ER) bypasses hexokinase/glucokinase.

**Regulation (high-yield; reciprocal with PFK-1)** - Activated by ATP and citrate. Glucagon also promotes activity indirectly, through lower fructose-2,6-bisphosphate (F2,6BP) via cAMP/PKA. - Inhibited by AMP and fructose-2,6-bisphosphate (F2,6BP). - F2,6BP is made by PFK-2 and degraded by FBPase-2. These are two domains of one bifunctional enzyme. - Fed state (insulin): the enzyme is dephosphorylated, PFK-2 is active, F2,6BP rises, PFK-1 is stimulated, and FBPase-1 is inhibited. Glycolysis is favored. - Fasting state (glucagon → cAMP → PKA): the enzyme is phosphorylated, FBPase-2 is active, F2,6BP falls, PFK-1 is inhibited, and FBPase-1 is activated. Gluconeogenesis is favored. - Metformin inhibits gluconeogenesis, partly via AMP-mediated inhibition of FBPase-1 and via inhibition of mitochondrial glycerol-3-phosphate dehydrogenase.

**Fructose-1,6-bisphosphatase deficiency (AR, FBP1 gene)** - Impaired gluconeogenesis from all substrates (lactate, glycerol, alanine, and fructose). Glycogen stores are intact, so glycogenolysis can initially maintain glucose. Hypoglycemia appears once glycogen is depleted. - Presentation: neonatal or infant fasting hypoglycemia, lactic acidosis (metabolic acidosis with elevated anion gap), hyperventilation, ketosis, hepatomegaly, hypotonia, and seizures. Episodes are often triggered by fasting, febrile illness, or fructose/sucrose ingestion. - Labs: elevated lactate, uric acid, and alanine. Ketones and glycerol are also high. - Differential: glycogen storage disease type I (von Gierke, G6Pase deficiency) also causes fasting hypoglycemia, lactic acidosis, and hepatomegaly. It also causes hyperlipidemia, hyperuricemia, and a "doll-like" face. GSD I does not improve with glucagon in the fasting state. In FBPase deficiency, glucagon is ineffective during fasting, but it can raise glucose in the fed state (glycogen present). Also differentiate hereditary fructose intolerance (aldolase B deficiency). - Hereditary fructose intolerance (aldolase B deficiency): fructose-1-phosphate accumulates, which depletes Pi and ATP and inhibits glycogenolysis and gluconeogenesis. Symptoms start after fruit/sucrose introduction (weaning), with vomiting, hypoglycemia, jaundice, and cirrhosis. FBPase-1 is itself inhibited in this setting. - Treatment: avoid fasting (frequent feeds, IV dextrose during acute episodes), correct acidosis, and restrict fructose, sucrose, and sorbitol. The prognosis is good if recognized early, and tolerance to fasting improves with age.

**Board pearls** - FBPase-1 is a key control point of gluconeogenesis, reciprocal to PFK-1 (the key control point of glycolysis). - Bifunctional PFK-2/FBPase-2 is controlled by insulin/glucagon. - Hypoglycemia plus lactic acidosis and hepatomegaly in a fasting infant: think GSD I or FBPase-1 deficiency. - Ethanol metabolism raises NADH/NAD+, which shunts pyruvate to lactate and oxaloacetate to malate. This impairs gluconeogenesis and causes fasting hypoglycemia.