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Chemistry 110 Bettelheim, Brown, Campbell & Farrell Ninth Edition Introduction to General, Organic and Biochemistry Chapter 23 Enzymes Proteins that catalyze specific reactions. Enzymes ¾All enzymes are proteins, with the exception of some RNAs that catalyze their own splicing. ¾Enzymes cause remarkable rate enhancements, the rate of a reaction can increase by a factor of up to 1020 over an uncatalyzed reaction, but they cannot make a reaction go that otherwise would not go. ¾Some enzymes catalyze the reaction of only one compound, others are stereospecific, for example, enzymes that catalyze the reactions of only L-amino acids or other specific types of compounds, others only one type of bond, for example, trypsin that catalyzes hydrolysis of peptide bonds formed by the carboxyl groups of lysine and arginine. ¾Most enzymes are specific for substrates. Enzymes are Grouped by Their Function Enzymes are classified into six major groups. ¾oxidoreductases: catalyze oxidation-reduction reactions. ¾transferases: catalyze group transfer reactions ¾hydrolases: catalyze hydrolysis reactions. ¾lyases: catalyze addition of groups to a double bond, or removal of groups to create a double bond. ¾isomerases: catalyze isomerization reactions. ¾ligases: catalyze the joining to two molecules. ¾Specific enzymes are commonly named after the reaction or reactions they catalyze, for example: lactate dehydrogenase, acid phosphatase. ¾Enzyme names always end in –ase . Terminology in Enzyme Chemistry ¾The apoenzyme is the protein part of an enzyme. ¾The cofactor is the nonprotein portion of an enzyme that is involved in a chemical reaction; examples are metallic ions such as Zn2+ and Mg2+. ¾A coenzyme is an organic cofactor for example heme. Sometimes enzymes require both kinds of cofactors. ¾A substrate is the compound or compounds whose reaction an enzyme catalyzes. ¾The active site is that specific portion of the enzyme to which a substrate binds during reaction. ¾Enzymes cause chemical equilibria to be established very rapidly, but the equilibrium composition is not changed. Enzyme Chemistry Terminology ¾Enzyme activation: any process that initiates or increases the activity of an enzyme. ¾Enzyme inhibition: any process that makes an enzyme less active or inactive. ¾Competitive inhibitor: any substance that binds to the active site of an enzyme thus preventing binding of substrate. ¾Noncompetitive inhibitor: any substance that binds to a portion of the enzyme other than the active site and thus inhibits the activity of the enzyme. ¾Enzyme Activity is a measure of how much a reaction rate is increased by the presence of the enzyme. ¾The rate of an enzyme-catalyzed reaction is affected by: 9enzyme concentration 9substrate concentration 9temperature 9pH Mechanism of Enzyme Action Enzyme + Substrate Enzyme-Substrate Complex Enzyme-Product Complex Enzyme-Substrate Activated Complex Enzyme + Product The Mechanism of Enzyme Action ¾Both the lock-and-key model and the induced-fit model emphasize the shape of the active site. ¾However it is the chemistry of the active site that is its most important aspect. ¾In more than 65% of the enzymes studies done to date, just five amino acids participate in the active sites. ¾These five amino acids are Histidine > Cystiene > Aspartic Acid > Arginine > Glutamic Acid. ¾Four of these amino acids have either acidic or basic side chains; the fifth has a sulfhydryl group (-SH). Enzyme Regulation & Feedback ¾Feedback control is an enzyme-regulation process where the product of a series of enzyme-catalyzed reactions inhibits an earlier reaction in a sequence. The inhibition may be competitive or noncompetitive. ¾A proenzyme or zymogen is an inactive form of an enzyme that must have part of its polypeptide chain cleaved before it becomes active. An example is trypsin, a digestive enzyme which is synthesized and stored as trypsinogen, which has no enzyme activity. It becomes active only after a six-amino acid fragment is hydrolyzed from the N-terminal end of its chain. Removal of this small fragment changes not only the primary structure but also the tertiary structure, allowing the molecule to achieve its active form. ¾Protein modification is similar. Here an enzyme has a group added or removed, usually a phosphoryl residue, to activate it. General Effects of Enzyme Inhibition ¾Antibiotics inhibit enzymes by affecting bacterial metabolism. ¾Nerve Gases cause irreversible enzyme inhibition – choline esterase inhibitors. ¾Insecticides – Most are reversible choline esterase inhibitors. ¾Many heavy metal poisons work by irreversibly inhibiting enzymes, especially cysteine residues. ¾Enzymes are commonly released from cells by injury or disease – detecting them confirm the injury or disease state. Enzyme Assays in Medicine Enzyme Assays are useful in the diagnosis of various diseases. Enzyme Body Fluid Disease Diagnosed Alanine aminotransferase (ALT) Serum Hepatitis Acid phosphatase Alkaline phosphatase (ALP) Amylase Serum Serum Serum Prostate cancer Liver or bone disease Pancreatic disease Aspartate aminotransferase (AST) Serum, Cerebrospinal fluid Lactate dehydrogenase (LDH) Serum Creatine phosphokinase (CK) Serum Phosphohexose isomerase (PHI) Serum Heart attack or hepatitis Heart attack Heart attack Heart attack Enzymes in Medicine ¾Enzymes can be used to assay blood for specific substances. ¾Immobilized enzymes provide simple tests for many diseases or conditions. ¾Enzyme activators may be used medically to activate zymogens or proenzymes – tissue plasminogen activator therapy causes conversion of plasminogen to plasmin to dissolve blood clots in heart attack and strokes.