Regulation of Metabolism
Local (intrinsic) Control Mechanisms
Enzymes and Cellular Energy
• Cellular metabolism consists of:
– Catabolism: the breakdown of organic molecules
– Anabolism: the synthesis of organic molecules
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Chemical Reactions
• Chemical reactions break and form chemical bonds.
• Breakdown and synthesis of organic molecules is accomplished through chemical reactions.
• The substance (or substances) initially involved in a biochemical reactions are called reactants. – Chemical reactions are usually characterized by a chemical change, and they yield one or more products, which usually have properties different from the reactants. – Products are formed as the chemical reaction progresses toward chemical equilibrium at a certain reaction rate 3
Chemical Reaction Rate
Reversible and Irreversible Reactions
Law of Mass Action
• The direction of a chemical reaction is determined in part by the concentrations of reactant and product.
• If a reaction is in equilibrium, it can be accelerated by adding reactance or removing products
– Adding glucose to a cell accelerates glycolysis
– Removing lactate accelerates lactate formation
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Metabolic Pathways
• Metabolic pathways are series of chemical reactions occurring within a cell. • In each pathway, a principal chemical is modified by a series of chemical reactions. – Enzymes catalyze these reactions
– Additional dietary minerals, vitamins, and cofactors are often required for pathway to function properly. • Numerous distinct metabolic pathways co‐
exist within a cell. Metabolic Pathways
• The metabolic pathway involves the step‐by‐
step modification of an initial molecule to form another product. The resulting product can be used in one of three ways:
(1) used immediately, as the end‐product of a metabolic pathway
(2) used to initiate another metabolic pathway
(3) stored by the cell
Metabolic Pathways
• A reactant molecule called a substrate enters a metabolic pathway – Depending on the activity of the cell and the availability of the substrate, the pathway can speed or slow
– The product of one reaction in the pathway is a substrate for the next reaction
– An increase in concentration of intermediates and/or end‐products may influence the metabolic rate for that particular pathway.
Metabolic Pathways
• Each metabolic pathway consists of a series of biochemical reactions that are connected by their intermediates: the products of one reaction are the substrates for subsequent reactions, and so on. Metabolic Pathways
• Metabolic pathways are often considered to flow in one direction. – Although all chemical reactions are technically reversible, conditions in the cell are often such that it is thermodynamically more favorable for flux to flow in one direction of a reaction. – One pathway may be responsible for the synthesis of a product; the breakdown may usually occur via a separate and distinct pathway. Enzymes and Cellular Energy
• Cellular metabolism consists of:
– Catabolism: the breakdown of organic molecules
– Anabolism: the synthesis of organic molecules
– Anabolic and catabolic often occur independently of each other, separated either physically by compartmentalization within organelles or separated biochemically by the requirement of different enzymes and co‐factors.
Regulation of Metabolic Pathways using Enzyme‐Mediated Reactions
• Metabolic pathways are regulated by three major factors:
– Substrate Concentration
– Enzyme Concentration (induce or inhibit protein enzyme formation – slow)
– Enzyme Activity
• Alter enzyme shape
– Allosteric modulation
– Alter pH
• Alter temperature in which enzyme functions
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Regulation of Metabolic Pathways
• End Product Regulation
– Accumulation of an end product of allosterically
directly alters activity of a rate limiting enzyme
• Occurs early in pathway
• A form of intrinsic negative feedback control
• Examples
– Presence of ADP increases activity of PFK in glycolysis
– Presence of ATP decreases activity PFK in glycolysis
– Presence of NADH increases activity of isocitric
dehydrogenase in the Krebs Cycle
Krebs cycle regulation
• The regulation of the TCA cycle is largely determined by substrate availability and product inhibition. • NADH, a product of all dehydrogenases in the TCA cycle with the exception of succinate dehydrogenase, inhibits pyruvate
dehydrogenase, isocitrate dehydrogenase, α‐ketoglutarate
dehydrogenase, and also citrate synthase. • Acetyl‐coA inhibits pyruvate dehydrogenase
• Succinyl‐CoA inhibits alpha‐ketoglutarate dehydrogenase and citrate synthase. When tested in vitro with TCA enzymes
• ATP inhibits citrate synthase and α‐ketoglutarate
dehydrogenase
• Citrate is used for feedback inhibition, as it inhibits phosphofructokinase, an enzyme involved in glycolysis that catalyses formation of fructose 1,6‐bisphosphate,a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme.
Ca++ regulation of metabolic pathways
• Krebs Cycle: Ca++ activates pyruvate
dehydrogenase, isocitrate dehydrogenase and α‐ketoglutarate dehydrogenase. • Glycogen breakdown to glucose
– Ca++ stimulates glycogen phosphorylase which catalyzes reaction:
glycogen  glycogen + glucose‐1‐phosphate
Extrinsic Regulation of Pathways
• Hormones and neurotransmitters influence substrate availability
– Adrenalin stimulates glycogen phosphorylase
activity:
glycogen  glycogen + glucose‐1‐phosphate