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1 Metabolism: The Regulation of Enzyme Activity and Synthesis I. II. Regulation A. Without adequate control of metabolic processes: Cells become disorganized and die B. Metabolic pathways are regulated so that: Cell components are present in correct amounts C. Chemical composition of cell's surroundings changes constantly: Microbial cell responds to environmental change by: Switching catabolic pathways when new nutrients become available D. Constitutive enzymes: Enzymes in metabolic pathways essential to life: Always present in cells E. Many enzymes not needed all the time: Cells regulate: Location Activity Synthesis Types of Regulation A. Three types 1. Metabolic Channeling: Important in eukaryotic cells: Compartmentalization: Metabolites and enzymes located in different parts of the cell: Differential distribution of enzymes among separate organelles Concentration gradients within the cytoplasm 2. B362 Control of Enzyme Activity Enzymes often stimulated or inhibited to rapidly alter pathway activity: Allosteric Regulation: Allosteric Enzymes: Regulatory enzymes Effector (modulator): Small molecule alters the activity of allosteric enzyme: Binds reversibly to allosteric site on enzyme: Changes conformation of the active site: Alters activity of the enzyme 2 Two types of effectors: Positive effector: Increases enzyme activity Negative effector: Decreases enzyme activity Allosteric inhibition: Feed back inhibition: End-product of pathway inhibits activity of first enzyme (pacemaker enzyme) in pathway: Enzyme's synthesis not affected: Activity of enzyme controlled: Enzyme combines with end-product of metabolic pathway: Active site blocked or its shape changed: Can no longer combine with its substrate: End product is not made Enzyme-end-product combination reversible: When more end product is needed enzyme is released: Synthesis can resume Catalytic activity of Allosteric enzymes: Regulated through reversible binding of endproduct to a site other than the active site Feedback relations may be very complex if branched pathways are involved In branched pathway first enzyme after branch is usually the allosteric enzyme Regulation of enzyme activity allows: Fine tune metabolic activity Rapidly adjust metabolic activity 3. B362 Regulation of enzyme synthesis: Number of enzyme molecules may be controlled: Involves controling expression of genetic material: 3 Covers longer time periods: Complements regulation of enzyme activity Saves energy and raw material Maintains balance between the amounts of various cell proteins Allows cells to adapt to long term environmental change III. Control of gene expression A. Involves Regulation of mRNA synthesis: Induction and repression Result from changes in rate of transcription: B. Induction: Enzyme synthesized only in presence of its specific substrate: Catabolic enzymes often induced In absence of lactose E. coli lacks: -galactosidase: Catalyzes the hydrolysis of lactose galactose and glucose mRNA that codes for the -galactosidase is not transcribed When carbon source is lactose: 3000 -galactosidase molecules present in cell: mRNA that codes for the -galactosidase is transcribed -galactosidase: Inducible enzyme Level rises in the presence of small molecule, the inducer Inducer: Substance which causes induction (allolactose derivative of lactose) C. Operon: Genes (and their controlling elements) located next to each other in the DNA molecule D. Operator gene: Area of DNA that controls RNA transcription B362 4 R P 0 A B C ────┴/\/\/\/\┴───┴─────┴─────┴──────┴───────┘ OPERON R = REPRESSOR GENE P = PROMOTER 0 = OPERATOR GENE I = INDUCER (allolactose) RP = REPRESSOR PROTEIN CR = CO-REPRESSOR (END-PRODUCT) E. Repressor protein: Synthesized all the time: Sits on operator gene: Blocks formation of mRNA No enzymes can be made F. Inducer (specific substrate): combines with repressor protein: Repressor protein no longer fits on the operator gene: mRNA is synthesized Protein (enzymes) is transcribed G. H. Enzymes allow cell to metabolize inducer Repression: Synthesis of enzyme occurs only when end-product of biochemical pathway is not present Repressor protein: Synthesized all the time: Can't combine with operator gene: Structural genes are transcribed: Enzymes necessary for biosynthetic pathway produced: Specific end-product formed When concentration of end-product increases: End-product combines with repressor protein B362 5 Combination of repressor protein and co-repressor (end-product) sit on operator gene and turn it off: No mRNA made: no enzyme is produced Enzyme production is repressed I. IV. Induction and repression: Common in bacteria Not common in eukaryotic cells CATABOLITE REPRESSION A. Occurs in bacteria and yeast: Presence of glucose inhibits synthesis of enzymes involved in the utilization of other sugars: Lactose Galactose Maltose Arabinose When glucose present with other sugars: Glucose always utilized first After glucose is used: Enzymes necessary for utilization of other sugars made. B. In operons subject to catabolite repression: RNA polymerase binds firmly to promoter: Only if catabolic activator protein (CAP) is already bound to the promoter C. Promoter: Region in DNA where RNA polymerase must bind before it can make the linkage between ribonucleotides and phosphate CAP only binds to promoter if first combined with cyclic adenosine monophosphate (cAMP) Presence of glucose causes: Large decrease in intracellular concentration of cyclic AMP Glucose inhibits synthesis or breaks down cAMP: In presence of glucose intracellular level of cAMP low: B362 6 CAP can't attach to promoter: RNA polymerase can't attach to promoter No RNA can be transcribed No protein synthesis occurs B362