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Prokaryotic Gene Regulation Regulation of Bacterial Gene Expression (a) Regulation of enzyme activity Precursor Feedback inhibition (b) Regulation of enzyme production Enzyme 1 Gene 1 Enzyme 2 Gene 2 Regulation of gene expression Enzyme 3 Gene 3 – Enzyme 4 Gene 4 – Enzyme 5 Gene 5 Tryptophan Figure 18.20a, b Metabolic Regulation 1. Adjust the activity of metabolic enzymes already present 2. Regulate the genes encoding the metabolic enzymes (a) Regulation of enzyme activity Precursor Feedback inhibition (b) Regulation of enzyme production Enzyme 1 Gene 1 Enzyme 2 Gene 2 Operons: functional gene clusters • In bacteria, genes are often clustered into operons, composed of – A promoter • Site for RNA-polymerase to bind and initiate transcription – An operator, the “on-off” switch Regulation of gene expression • Region of DNA within the promoter or between the promoter and the first gene Enzyme 3 Gene 3 – The genes for metabolic enzymes – • Usually a set of enzymes catalyzing different steps in a common metabolic pathway • All the genes in the operon set are transcribed onto a single, common mRNA Enzyme 4 Gene 4 – Enzyme 5 Gene 5 Tryptophan Figure 18.20a, b Operons: functional gene clusters Regulation of Bacterial Gene Expression • Conserve energy — Metabolism is precisely regulated – Make only proteins needed at a specific time • Non-regulated gene expression – RNA-poly binds freely to promoter – Constitutive genes— Enzymes always needed (e.g., glycolysis) • Negative gene regulation – Repressor protein binds operator → Block RNA polymerase → Inhibits gene expression → Decreases synthesis of enzymes • Positive gene regulation – Activator protein binds separate binding site near promoter → Enhance RNA polymerase activity • Regulon: multiple operons regulated by the same regulator. – >40 regulons identified in E. coli Heyer 1 Prokaryotic Gene Regulation Negative gene regulation The operon default is usually turned “on” Repressor protein binds operator → Block RNA polymerase → Inhibits gene expression → Decreases synthesis of enzymes Negative gene regulation Regulating the regulator: • In a repressible operon – A corepressor molecule binds allosterically to the repressor protein → repressor protein assumes active configuration → binds to the operator → shuts off transcription • In an inducible operon – A inducer molecule binds allosterically to the repressor protein → repressor protein assumes inactive configuration → cannot bind to the operator → turns on transcription (a) Regulation of enzyme activity Repressible Operon Feedback inhibition (b) Regulation of enzyme production Precursor Enzyme 1 Gene A Enzyme 2 Gene B • • • • • Heyer Tryptophan operon Usually occurs in anabolism Consists of 5 structural genes Repressor is inactive so tryptophan is synthesized Amino acid in media – Binds to repressor activating it Regulation of gene expression trp operon Enzyme 3 Gene C – Enzyme 4 Gene D – Enzyme 5 Gene E Tryptophan 2 Prokaryotic Gene Regulation trp operon trp operon DNA trp operon Promoter trpR DNA Regulatory gene mRNA 5′ 3′ Genes of operon trpD trpC trpE Operator RNA Start codon Stop codon polymerasemRNA 5′ E Inactive repressor Protein No RNA made Promoter D C trpB trpA mRNA B A Polypeptides that make up enzymes for tryptophan synthesis (a) Tryptophan absent, repressor inactive, operon on. RNA polymerase attaches to the DNA at the promoter and transcribes the operon’s genes. Figure 18.21a Active repressor Protein Tryptophan (corepressor) (b) Tryptophan present, repressor active, operon off. As tryptophan accumulates, it inhibits its own production by activating the repressor protein. Figure 18.21b lac Operon Inducible Operon • • • Turn on the transcription of gene Inducer- induces transcription Inducible enzymes – Synthesized only when substrate is present – Lactose metabolism in E. coli • Inducible operon: enzymes to metabolize lactose • Regulatory sites – Promoter- RNA polymerase – Operator- repressor binds • i genes code for repressor-regulatory protein – Outside operon – Always turned on (constitutive gene) – Binds to operator • Structural genes – lac operon-3 genes lac Operon * *Genes coding for enzymes to digest and utilize lactose: Z ⇒ β-galactosidase Y ⇒ permease A ⇒ transacetylase Heyer 3 Prokaryotic Gene Regulation Lactose in Medium • • • • Binds repressor changing shape Repressor can’t bind to Operator RNA polymerase can bind to Promoter Enzymes for lactose metabolism produced – Lactose transported into cell – Metabolized into glucose and galactose lac Operon lac Operon lac operon Promoter Regulatory gene Operator lacl DNA 3′ mRNA 5′ No RNA made mRNA RNA polymerase 5′ Active repressor lacY lacA RNA 3′ polymerase mRNA 5' 5′ mRNA β-Galactosidase Permease Protein Allo-lactose (inducer) Protein lacz lacl DNA lacZ Transacetylase Inactive repressor (b) Lactose present, repressor inactive, operon on. Allo-lactose, an isomer of (a) Lactose absent, repressor active, operon off. The lac repressor is innately lactose, derepresses the operon by inactivating the repressor. In this way, the enzymes for lactose utilization are induced. active, and in the absence of lactose it switches off the operon by binding to the operator. Figure 18.22a Positive Gene Regulation • Some operons are also subject to positive gene regulation – Stimulatory activator protein binds separate binding site near promoter → Enhance RNA polymerase activity → Increase gene expression & enzyme synthesis Figure 18.22b Positive regulation of the lac operon • In E. coli, when glucose is the preferred energy substrate. • When available glucose decreases, intracellular cAMP (cyclic-adenosine diphosphate) increases. • cAMP binds to CAP, causing it to change into the active configuration. • Active CAP enhances operon promoters for alternative catabolic pathways, including the lac operon. – Catabolite Activator Protein (CAP) • Activates many catabolic pathways • Including lac operon. Heyer 4 Prokaryotic Gene Regulation Positive regulation of the lac operon • The lac operon is activated by the binding of CAP Promoter Positive regulation of the lac operon • ↑glucose levels → ↓cAMP → inactive CAP Promoter DNA DNA lacl lacZ CAP-binding site Active CAP cAMP Inactive CAP RNA polymerase can bind and transcribe lacl lacZ CAP-binding site Operator Operator RNA polymerase can’t bind Inactive CAP Inactive lac repressor (a) Lactose present, glucose scarce (cAMP level high): abundant lac mRNA Inactive lac repressor (b) Lactose present, glucose present (cAMP level low): little lac mRNA synthesized. synthesized. Figure 18.23a Combined Negative & Positive Regulation of the lac Operon 1. Low lactose → repressor active → operon suppressed 2. High lactose/high glucose → repressor inactive but activator inactive → low operon activity 3. High lactose/low glucose → repressor inactive and activator active → high operon activity → enhanced lactose catabolism Figure 18.23b Arabinose Operon • Negative or Positive gene regulation? • Repressible or Inducible? Arabinose Operon Heyer 5