Pyruvate transport, Malate and Aspartate Shuttle, and Gluconeogenesis PDF

Pyruvate transport  Pyruvate transport Pyruvate transport and metabolism in the cell. Pyruvate is derived from glucose, lactate, malate, and amino acids (aa). Under aerobic conditions, pyruvate enters the mitochondrion by crossing the outer membrane (OM) via porins...

Pyruvate transport  Pyruvate transport Pyruvate transport and metabolism in the cell. Pyruvate is derived from glucose, lactate, malate, and amino acids (aa). Under aerobic conditions, pyruvate enters the mitochondrion by crossing the outer membrane (OM) via porins, and the inner membrane (IM) via the mitochondrial pyruvate carrier (MPC) complex. Once inside, it enters the tricarboxylic acid (TCA) cycle to provide energy or intermediates for other biosynthetic reactions. Under hypoxic conditions, pyruvate is reduced to lactate in the cytosol, which is then secreted. PEP: phosphoenolpyruvate; LDH: lactate dehydrogenase; MCT: monocarboxylate transporters; α-KG: α-ketoglutarate; GDH: glutamate dehydrogenase.  Malate and Aspartate Shuttle Shuttle pathways for transporting oxaloacetate from mitochondria into the cytosol. The shuttles are named for the molecule that actually moves across the mitochondrial membrane. 1 and 3=malate dehydrogenase; 2=malate translocase; 4 and 7=aspartate aminotransferase; 5=glutamate dehydrogenase; 6=aspartate translocase.  Mitochondrial pyruvate carrier 2 (MPC2) also known as brain protein 44 (BRP44) MPC2, BRP44, mitochondrial pyruvate carrier 2, SLC54A2, 1q24.2 MPC2 This protein is involved in transport of pyruvate across membrane of mitochondria is encoded by the MPC2 gene. Gluconeogenesis Gluconeogenesis is the re-synthesis of glucose - Gluconeogenesis is the process by which glucose is MADE from small, non- carbohydrates - Provides the source of blood glucose other than glycogen to prevent hypoglycemia - Major users of glucose: brain and muscles  1. Need relative large amount of Energy 2. Does not have significant energy store Brain 3. Dependent on blood glucose as energy source 4. Not sensitive to hormone regulation 5. Can adapt to use ketone body (fatty acids) but only after prolonged fasting  Human brain alone requires about 130 g of glucose per day, out of about 200 g needed by the entire body. During prolonged starvation, the rate of gluconeogenesis depends Brain on Increased alanine levels in liver. The stored glycogen is depleted within the first 12-18 hours of fasting.  Major producers of glucose: Liver (90%) and Gluconeogenesis kidney (10%) Major gluconeogenic precursors in mammals (1) Lactate and pyruvate (2) Most amino acids (especially alanine) (Muscle proteins break down and aa transported to liver) (3) Glycerol (from triacylglycerol hydrolysis)  - Any metabolite that can be converted to pyruvate or oxaloacetate can be a glucose precursor Gluconeogenesis - Gluconeogenesis is a reversal glycolysis which employs 4 + 2 new steps to avoid “irreversible steps” of glycolysis.  Irreversible and regulated steps of glycolysis Hexokinase 1,3, and 10 Phosphofructokinase Pyruvate kinase  Synthesis of 1 mole of glucose from 2 moles of pyruvate needs 6 moles of ATP and 2 moles of NADH Gluconeogenesis enzymes are cytosolic except: ATP of gluconeogenesis (1) Glucose 6-phosphatase (endoplasmic reticulum) (2) Pyruvate carboxylase (mitochondria)  1- Substrate cycle - two opposing enzymes: Regulation of (1) Phosphofructokinase-1 (glycolysis) Gluconeogenesis (2) Fructose 1,6-bisphosphatase (gluconeogenesis)  2- Energy level (ATP vs AMP level) of cell dictates which pathway is on. Regulation of When cellular ATP is high (AMP would then be Gluconeogenesis low), glucose is not degraded to make ATP. It is more useful to the cell under such conditions to store glucose as glycogen. Phosphofructokinase (Glycolysis) is inhibited by ATP and stimulated by AMP. Regulation of Stimulation Gluconeogenesis glucagon acetyl CoA citrate Inhibition NADH/NAD+ ratio alcohol may cause elevated NADH/NAD+ ratio leading to hypoglycemia Regulation of Gluconeogenesis