Enzymes: Regulation 2-3
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1 Enzymes: Regulation 2-3 Reversible covalent modification Association with regulatory proteins Irreversible covalent modification/proteolytic cleavage Reading: Berg, Tymoczko & Stryer, 6th ed., Chapter 10, pp , Chapter 14, pp Problems: pp , Chapter 10: #7, 10, 12, 13 Key Concepts Activities of many key enzymes are regulated in cells, based on metabolic needs/conditions in vivo. Regulation of enzyme activity can increase or decrease substrate binding affinity and/or k cat. 5 ways to regulate protein activity (including enzyme activity): 1. allosteric control 2. multiple forms of enzymes (isozymes) 3. reversible covalent modification -- example: phosphorylation/dephosphorylation phosphorylation (phosphoryl transfer from ATP to specific -OH group(s) on protein) catalyzed by protein kinases dephosphorylation (hydrolytic removal of the phosphate groups) catalyzed by protein phosphatases 4 interaction with regulatory proteins examples: 4. interaction with regulatory proteins examples: protein kinase A (PKA) Ca 2+ -calmodulin-dependent kinases 5. irreversible covalent modification, including proteolytic activation (zymogen activation) examples: digestive proteases like chymotrypsin and trypsin blood clotting cascade Enzymes: Regulation 2-3 1
2 Enzyme Regulation cont d 3. Reversible Covalent Modification Modification of catalytic or other properties of proteins by covalent attachment of a modifying group modification catalyzed by a specific enzyme. modifying group removed by a different enzyme Enzymes can cycle between active and inactive (or more and less active) states by chemical modification. allosteric regulation: an immediate and localized response, so rapid activity changes covalent modifications: slower and longer-lasting effects with coordinated systemic effects (e.g., a single hormone can trigger covalent modification events that change activities of metabolic enzymes in a many tissues and cells.) Activities of modifying/demodifying enzymes themselves are regulated, allosterically (making process sensitive to changes in concentration of small molecules that act as "signals"), or by another reversible covalent modification process, or both. Enzymes: Regulation 2-3 2
3 Phosphorylation/dephosphorylation probably the most common means of regulating enzymes, membrane channels, virtually every metabolic process in eukaryotic cells Phosphorylation Kinases: catalyze phosphoryl transfer involving ATP (usually) named for molecule that "receives" phosphate group e.g., hexokinase transfers terminal phosphate from ATP to a variety of hexose sugars like glucose ( glucose-6-phosphate). General reaction catalyzed by kinases: (target) R-OH + ATP <==> R-OPO ADP Protein kinases: kinases that transfer phosphoryl group from ATP to a Ser-OH, Thr-OH, or Tyr-OH on a target protein) Dephosphorylation h phosphate group removed by hydrolysis of phosphate ester (transfer of phosphate to H 2 O) Dephosphorylation of enzymes is catalyzed by a specific PROTEIN phosphatase. Protein Kinases VERY important regulatory components in eukaryotic cells G o << 0 (equilibrium lies far to right) Kinase reactions essentially irreversible can t make ATP this way Berg et al., p. 285 Enzymes: Regulation 2-3 3
4 2 classes of protein kinases: 1. Serine/Threonine protein kinases: recipient group on target protein is a Ser-OH or Thr-OH. 2. Tyrosine kinases: recipient group on target protein is a Tyr-OH. Recipient (target) protein's properties/conformation/activity altered by phosphorylation Often, phosphorylation causes subtle conformational change that (if target is an enzyme) increases or decreases catalytic activity, or causes target to interact (or not to interact) with some other cellular component. Protein kinases themselves are regulated, often by allosteric effects of a small signaling molecule, as in the examples below: PROTEIN PHOSPHATASES catalyze hydrolysis of phosphate ester bonds in phosphorylated target proteins = dephosphorylation Equilibrium lies far to the right -- irreversible in 55.5 M H 2 O. Dephosphorylation is NOT the reverse of protein kinase-catalyzed phosphorylation reaction. Both types of reaction are irreversible. (Active) catalyst (kinase or phosphatase) needed for significant reaction rates, so Cell's "decision" about what fraction of target protein is phosphorylated vs. dephosphorylated depends on how active the specific protein kinase is vs. how active the specific protein phosphatase is. Enzymes: Regulation 2-3 4
5 "Cycles" of phosphorylation/dephosphorylation hydrolyze ATP: 1. Target protein-oh + ATP Target protein-opo ADP 2. Target protein-opo H 2 O HOPO Target protein-oh 3. Net reaction: ATP + H 2 O ADP + HOPO 2 3 (hydrolysis of ATP) Standard free energy change, G ' = 31 kj/mol, but Actual free energy change under cellular conditions G' = ~ 50 kj/mol. High negative free energy change makes phosphorylation/dephosphorylation cycle unidirectional in cell (essential for a process whose rate is being regulated) 2 effects of large negative G' for protein phosphorylation: 1. Some of net negative free energy Change from phosphoryl transfer makes reaction irreversible. 2. Some free energy is conserved in the phosphorylated protein -- phosphorylation of even one site on a protein can shift conformational equilibrium in protein structure by a large factor, say The 2 conformations can have very different catalytic or kinetic properties. Biochemical Cascades: cellular/biochemical processes with multiplicative effects Cascade: a series of events in which each event in series is catalyzed by an enzyme activated in previous event. First event triggered by some signal that initiates cascade, e.g., a hormone binding to a receptor, or a wound triggering the blood clotting cascade Cascade produces rapid and enormous amplification of original signal because every activated enzyme molecule can itself catalyze conversion of many substrates (substrates often = other enzymes). Example: Suppose one signaling molecule triggers activation of one molecule of Enzyme 1. Single molecule of active Enzyme 1 activates 100 molecules of Enzyme 2. Each of the 100 molecules of active Enzyme 2 activates 100 molecules of Enzyme 3. Each of those 10,000 molecules of active Enzyme 3 activates 100 molecules of Enzyme 4. The 10 6 molecules of active Enzyme 4 each activates 100 molecules of Enzyme 5 -- we're up to 100 million active Enzyme 5 molecules! Real cascades involve a lot more than 100 products per enzyme molecule, with very rapid reactions, so geometric progression produces rapid and enormous response. Enzymes: Regulation 2-3 5
6 Adenylate Cascade and Protein Kinase 4. Interaction with regulatory proteins (Chapter 14, pp ) Protein Kinase Cascades Phosphorylation as a control mechanism highly amplified effects: One single activated protein kinase molecule can phosphorylate hundreds of target proteins in a very short time. If target proteins themselves are enzymes activated by phosphorylation, each activated enzyme then can carry out many, many catalytic cycles on its substrate. Result of cascade: a major multiplicative effect between starting signal (say, one small molecule binds to one protein kinase molecule to activate it) and final outcome several steps away Enzymes: Regulation 2-3 6
7 Protein Kinase Specificity Some protein kinases "multifunctional" -- phosphorylate many different target proteins A particular kinase always phosphorylates a residue in a specific sequence or a "consensus" sequence. (Sequences phosphorylated by that kinase very similar but not all identical). example: consensus sequence in all target proteins phosphorylated by protein kinase A: Ser or Thr in this consensus sequence:. Arg Arg X Ser Z or. Arg Arg X Thr Z X = a small amino acid residue; Z = a large hydrophobic residue Protein Kinase A binds other substrate protein sequences with a much lower affinity, so doesn't phosphorylate them very often. Other protein kinases are very specific not only for local sequence but also for 3-dimensional structure around it, and phosphorylate only a single target protein or a small number of closely related target proteins. Protein Kinase A great example of integration of allosteric regulation and regulation by reversible covalent modification (phosphorylation) How does camp activate PKA? camp binding alters quaternary structure of protein kinase A. PKA inactive form (without camp bound): 2 catalytic subunits + 2 regulatory subunits. regulatory subunits inhibitory -- C 2 R 2 quaternary form can't phosphorylate targets. camp binding to R subunits makes R s dissociate from C subunits. Berg et al., 5th ed., Fig (similar to 6th ed. Fig ) Enzymes: Regulation 2-3 7
8 PKA: How does R binding keep C subunits inactive? Specific AA sequence in R subunit of PKA that binds to the C subunit is actually a pseudosubstrate sequence:. Arg Arg Gly Ala Ile Compare with consensus sequence where PKA phosphorylates targets:. Arg Arg X Ser Z or. Arg Arg X Thr Z X = a small amino acid residue; Z = a large hydrophobic residue But R subunit sequence has Ala instead of Ser or Thr, so can't be phosphorylated. Knowing the sequence info above, to what part of PKA catalytic subunits structure would regulatory subunits bind? (How would that binding inhibit C subunit activity?) Summary: camp binds to R subunits conformational change, affects subunit interface. reduces binding affinity it of R (inhibitory) subunits for C subunits. (camp)r-r(camp) complex dissociates from C subunits, releasing the 2 C s Individual C subunits active when free Structure of protein kinase A catalytic subunit bound to Mg 2+ ATP and a 20-residue pseudosubstrate peptide inhibitor (structure determined by X-ray crystallography) Berg et al., 5th ed., <--- Fig Berg et al.,6th ed. Fig > ATP Mg 2+ + part of inhibitor bound in deep cleft between 2 "lobes" of protein, ATP bound more to one lobe, inhibitor binding more to other lobe Substrate peptide binding lobes move closer together (conformational change/induced fit). Restricting domain closure used to regulate protein kinase activity. Essentially all known protein kinases have conserved same catalytic core, residues (out of 350 residues total) of PKA catalytic subunit Enzymes: Regulation 2-3 8
9 Adenylate Cascade and Activation of Protein Kinase A by cyclic AMP (camp) 1. Regulatory cascade starts with hormone binding to extracellular receptor conformational changes in membrane proteins 2. Signal transduction (communication from one protein to another) activation of adenylate cyclase 3. adenylate cyclase: enzyme catalyzing intracellular production of cyclic AMP (camp) by cyclization starting with ATP as substrate camp: a small molecule (a nucleotide) 4. camp activates protein kinase A (PKA, aka "camp-dependent protein kinase"). camp an important intracellular signaling molecule in both prokaryotic and eukaryotic cells. camp = a "second messenger": signaling molecule whose production is under the control of other "messengers" such as hormones coming to the cell from the extracellular environment Primary role camp: activation of protein kinase A. 5. Active PKA then phosphorylates specific target proteins many different effects in the cell. Major amplification effect of PKA activation: each activated molecule of PKA can phosphorylate a LOT of molecules of target proteins. The adenylate cyclase cascade Berg et al., Fig Enzymes: Regulation 2-3 9
10 Example 2: Ca 2+ -Calmodulin and CAM-Dependent Kinases Ca 2+ a ubiquitous cytosolic messenger (signaling molecule). Ca 2+ concentration "sensed" by Ca 2+ -binding proteins that communicate signal to other proteins by protein-protein interactions. Examples: Calmodulin (CaM) Troponin C (TnC, protein homologous to CaM in muscle cells, regulating contraction in response to Ca 2+ ) Calmodulin (CaM; M r 17,000): example of a [Ca 2+ ]-sensing protein changes conformation when it binds Ca 2+ In Ca 2+ -bound form, CaM binds to and regulates activities of many CaMdependent proteins -- enzymes, pumps, etc. Mode of binding of Ca 2+ to calmodulin (CaM) Berg et al., Fig > Ca 2+ coordinated to 6 O atoms from protein and 1 O atom from H 2 O (top) CaM structure 4 high-affinity Ca 2+ binding sites each site in an "EF hand" structural motif EF hand motif formed by helix-loop-helix unit common Ca 2+ binding motif Repeating Ca 2+ binding motifs in structure of CaM CaM: 2 domains, each with 2 EF hand Ca 2+ -binding motifs Ca 2+ = green sphere 2 domains connected by flexible helix Berg et al., Fig Berg et al., Fig Enzymes: Regulation
11 Conformational changes in calmodulin on calcium binding In absence of Ca 2+, EF hands have hydrophobic cores buried inside the protein. Binding of Ca 2+ to each EF hand structural changes that expose hydrophobic patches on CaM surface. Hydrophobic patches serve as "docking regions" for binding target proteins. Central helix in CaM flexible even in the Ca 2+ -bound state folds back on itself when the 2 Ca 2+ domains of CaM bind to target proteins Target proteins all have a positively charged, amphipathic -helix Ca 2+ -CaM binds to positively charged, amphipathic helices in the enzymes it regulates. CaM kinase peptide, purple Berg et al., Fig a (blocks access of ATP to active site in this conformation) (Target protein activated by Ca 2+ -CAM) Ca 2+ -CaM binding to target enzyme s amphipathic helix stabilizes activated conformation of target enzyme. After Ca 2+ binding (step 1), 2 halves of Ca 2+ -CaM clamp down around target amphipathic helix in CaM Kinase I (step 2), binding it through hydrophobic and ionic interactions. Result: "extraction" of C-terminal helix in CaM kinase I so it s no longer blocking active site active conformation of CaM kinase I (conformation that can bind ATP). Berg et al., Fig b Enzymes: Regulation
12 5. Regulation of Enzyme Activity by Specific Proteolytic Cleavage Some enzymes biosynthesized as catalytically inactive precursor polypeptide chains Precursors fold in 3 dimensions Later activated by enzyme-catalyzed cleavage (hydrolysis) of 1 or more specific peptide bonds ZYMOGENS (or proenzymes): inactive precursors zymogen activation: cleavage/activation process Examples: 1) mammalian digestive enzymes More examples of enzymes/proteins activated by specific proteolysis 2) blood clotting: a cascade of proteolytic activations ( rapid response, with lots of amplification) 3) some protein hormones synthesized as inactive precursors e g insulin synthesized as proinsulin e.g., insulin -- synthesized as proinsulin final hormone generated by specific proteolysis to remove a peptide 4) collagen a fibrous protein (water-insoluble) synthesized as procollagen, a water-soluble precursor 5) apoptosis (programmed cell death) mediated by caspases: proteases synthesized as procaspases proteases synthesized as procaspases activated by regulatory signals 6) many developmental processes controlled by precisely timed activation of proenzymes Enzymes: Regulation
13 1) digestive enzyme activation Chymotrypsin as example Zymogen = chymotrypsinogen (Berg et al., Figs and 10-21) Secretion of zymogens by pancreatic acinar cells (1st clip activity) (diffuse away) Proteolytic activation of chymotrypsinogen: First cleavage (catalyzed by trypsin) between Lys15 and Ile16 generates new -amino group on Ile16 Conformational change results: new N-terminus of larger product chain (Ile16 residue) turns inward and makes new salt link that stabilizes the active conformation of chymotrypsin: Conformational change 1. formation of substrate specificity site (hydrophobic pocket where "R1" specificity group of substrate binds) 2. "completion" of orientation of groups to form oxyanion hole (for tight binding of transition states in acylation/deacylation mechanism.) (1st clip activity) Berg et al., Fig Enzymes: Regulation
14 Zymogenic Activation Cascade The Importance of Control of Zymogen Activation Trypsin initiates activation of all the pancreatic zymogens. Enteropeptidase, enzyme secreted by cells that line the duodenum (small intestine), activates a small amount of trypsinogen to trypsin, which coordinates control of zymogen activation outside cells. What would happen if even a few zymogen molecules, especially trypsinogen, were accidentally activated INSIDE the pancreatic acinar cells? What prevents premature activation of pancreatic zymogens inside cells? Small, very specific, very tight-binding inhibitor proteins inside cell inhibit any protease molecule that's accidentally prematurely activated. example: pancreatic trypsin inhibitor, PTI (6000 M.W.) Enzymes: Regulation
15 "PTI" binds VERY tightly to trypsin -- not even 8 M urea or 6 M guanidine HCl dissociate the complex! Part of PTI binds in active site of trypsin, with a Lys residue of PTI occupying R1 "specificity pocket". Pancreatic trypsin inhibitor is a substrate, but the peptide bond "after" that Lys is cleaved only VERY slowly (time scale of months). Combination of very tight binding and very slow catalytic turnover makes PTI a very effective inhibitor. Another tight-binding protease inhibitor helps prevent emphysema. Emphysema results from loss of elasticity (elastic fibers and other connective tissue proteins) in alveolar walls of the lungs, so CO 2 can't be exhaled effectively, so there isn't room for inhaling much fresh air (O 2 ). Neutrophils (white blood cells that engulf invading bacteria) secrete elastase. Excess elastase in blood plasma can hydrolyze elastic fibers in alveolar walls of the lungs emphysema. To prevent elastase from running amok in plasma, liver makes and secretes a plasma protein, 1 -antiproteinase (used to be called 1 - antitrypsin, but that s a misnomer it binds much tighter to elastase than to trypsin). 1 -antiproteinase in blood plasma keeps elastase inhibited, protecting lungs from damage. Enzymes: Regulation
16 Consequences of 1 -antiproteinase deficiency Inherited disorders: defects either in its structure, making it less effective as an inhibitor, or slowing down its secretion from liver and thus reducing its concentration in plasma 1. genetic deficiency in 1 -antiproteinase increased probability of developing emphysema. 2. Cigarette smoke damages the inhibitor. Component of cigarette smoke oxidizes a Met residue in 1 - antiproteinase that's required for binding to elastase (oxidation non-functional inhibitor) Result: smokers continually inactivate 1 -antiproteinase in their lungs and thus are also much more likely to develop emphysema. Imagine the results of a combination of a genetic deficiency and cigarette smoke! Learning Objectives Terminology: camp, consensus sequence, pseudosubstrate, cascade, reciprocal regulation, zymogen Describe in general terms how cells carry out reversible covalent modification of enzymes, and how the modification would be removed. Name ( generic names) the types of enzymes that catalyze phosphorylation and dephosphorylation of proteins, specify what types of amino acid functional groups are generally the targets of phosphorylation, and show the structure of such an enzyme functional group before and after phosphorylation. Explain whether the dephosphorylation reaction is actually the chemical reverse of the phosphorylation reaction, and if not, what type of reaction the dephosphorylation represents. Explain the regulation of protein kinase A (PKA) activity by camp, including gquaternary structural changes in PKA triggered by camp binding. What is a "pseudosubstrate" and how does it relate to the role of the regulatory subunits in PKA? Briefly discuss the structure of calmodulin (± Ca 2+ ), including structure of the EF hand motif, and how Ca 2+ -calmodulin activates target proteins as an example of how a regulatory protein works. Enzymes: Regulation
17 Learning Objectives, continued Describe the general mechanism by which zymogens are activated active enzymes. Briefly describe the structural change that occurs upon the activation of chymotrypsinogen, including what changes occur in the active site. Discuss the protective mechanism that keeps prematurely activated pancreatic digestive enzymes inside the acinar cells from autodigesting the pancreas, and describe/name an example. Give an example of a protease inhibitor that inhibits elastase. Explain how a deficiency (or an inactivating chemical event) in 1 - antiproteinase (formerly called 1 -antitrypsin) contributes to emphysema. Explain how a cascade of catalysts (e.g., in PKA activation, or in blood clotting) results in amplification of a signal. Enzymes: Regulation
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