Carbohydrate Synthesis in Animals

ANABOLISM I Carbohydrates Carbohydrate Synthesis in Animals 2 Gluconeogenesis Gluconeogenesis: Making “New” Glucose Precursors: From what compounds can glucose be made? • Animals can produce glucose from sugars or proteins. –sugars: pyruvate, lactate, or oxaloacetate –protein: from amino acids that can be converted to citric acid cycle intermediates (or glucogenic amino acids) • Animals cannot produce glucose from fatty acids. –product of fatty acid degradation is acetylCoA coming from fatty acids and ketogenic amino acid –There is no net conversion of acetyl-CoA to oxaloacetate in Kreb’s Cycle Plants, yeast, and many bacteria use the Kornberg Cycle to convert acetyl-CoA to succinate, thus producing glucose from fatty acids. 3 1 Gluconeogenesis •Blood glucose is largely made in the liver, although other organs can reverse glycolysis, but not deliver free glucose into the blood •Synthesis of glucose from simpler compounds: called gluconeogenesis •Operates only if ATP and NADH are plentiful The Cori Cycle • Other tissues deliver carbon to liver from “waste” products (Ala and Cori Cycles). As you can see the two pathways operate in different tissues, but how is this controlled in a single cell? 4 Gluconeogenesis Glycolysis versus Gluconeogenesis Glycolysis occurs mainly in the muscle and brain. • Opposing pathways that are both thermodynamically favorable: • Glycolysis: DG°’ = –35 kcal/mol • Gluconeogenesis: DG°’=–9 kcal/mol 7 PGI 6 5 Aldolase TIM 4 GAPDH 3 PGK 2 PGM 1 Enolase – operate in opposite direction • end product of one is the starting compound of the other • Seven Reversible reactions are used by both pathways. • Three ”glycolysis-specific” steps are reversed with Four “gluconeogenesis-specific” steps. Gluconeogenesis occurs mainly in the liver and kidney cortex. • Irreversible reactions of glycolysis must be bypassed in gluconeogenesis. – no ATP generated during gluconeogenesis; instead, 6 ATPs and 2 NADH needed per Glc. – Some different enzymes results in the different pathways – differentially regulated to prevent a futile cycle Let's look at the energetics of making glucose….. 5 2 Gluconeogenesis G3P Changes in Free Energy During Glycolysis and the Citric Acid Cycle PEP Pi 3PGA Favorable energetics for Calvin Cycle Pyruvate Pi Favorable energetics for Gluconeogenesis There are then 3 points that are novel for gluconeogenesis: 1. PyruvateàPEP (complicated) 2. Fru 1,6-P2 à Fru 6-P + Pi 3. Glc 6-Pà glucose + Pi 6 Gluconeogenesis The First Gluconeogenic Steps Travel Through Mitochondria 3’ • There are two ways from pyruvate to PEP. 5’ • Best place to assess whether there is ample ATP and NADH is the mitochondria. • Both ways go through mitochondria as that is the only place that has pyruvate carboxylase 4 6 TCA Cycle 5 citrate synthase 2 Acetyl-CoA 3 • The inner mitochondrial membrane is selectively permeable: Malate, PEP, and pyruvate, while oxaloacetate cannot escape. • Oxaloacetate can be utilized in the citric acid cycle (Kreb’s cycle) if needed. 2 pyruvate dehydrogenase Com plex 1 There are two new enzymes here….. 1 • Oxaloacetate can be converted to PEP or Malate in the mitochondria, then transported to cytosol for gluconeogenesis. • Will discuss the decision that pyruvate must make later….. 7 3 Gluconeogenesis Pyruvate to Phosphoenolpyruvate 8 Dr. Kornberg: Dr. Kornberg: Lecture 03.22.17 Lecture 03.22.17 (8:08(10:12-11:36) 1.5 min 11:36) 3.5 min 4