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Allosteric Regulation Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Chapter 15 Essential Questions • Before this class, ask your self the following questions: Reginald H. Garrett – What are the properties of regulatory enzymes? Enzyygme Regulation Charles M. Grisham • How do you know this enzyme is a regulatory enzyme? – How do regulatory enzymes sense the momentary needfll?ds of cells? ?Դৣ • How signal is delivered ᑣ٫݅ ፐำᆛઠ – Wha t mo lecu lar mec han isms are used to regu la te enzyme activity? http://lms. ls. ntou. edu. tw/course/106 [email protected] 2 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Outline 15. 1 – What Factors Influence Enzymatic Activity? • Part 1 Factors that influence enzymatic activity 1. The availability of substrates and cofactors! – Zymogen, isozyme and covalent modification! 2. Product accu m ul ates b the rate will dec r ease! • Part 2: The general features of allosteric 3. The amount of enzyme present at any moment – Genetic regulation of enzyme synthesis and decay regulation 4. Regulation of Enzyme activity – The mechanisms of allosteric regulation – Zymogens, isozymes , and modulator proteins may play – Example of a enzyme controlled by both a role allosteric regulation and covalent modification – Enzyme activity can be regulated through covalent modification • Part 3: Special focus on hemoglobin and – Allosteric Regulation myoglbilobin 3 4 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Regulation 1: Zymogen … The proteolytic activation of chymotrypsinogen • Zymogens are inactive precursors of enzymes. • TillTypically, pro tltiteolytic cleavage produces the active enzyme. Figure 15.2 Proinsulin is an 86-residue precursor to insulin 5 6 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Proteolytic Enzymes of the How to stop bleeding? Digestive Tract • Hbldlt?How our blood clot? – What is clotted? – Fibrinogen b Fibrin – the result of a series of zyygmogen activations Ann Ny Acad Sci 2001 Mosesson 7 8 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Aggregation of Fibrin Two routes to blood clot formation • The Cascade • ItiIntrins ic pa thway activation of seven – blood physically clotting factors contact w ith make fibrinogen abnormal quickly transformed surfaces caused into fibrin! by injury • kallikrein, XIIa, XIa, • Extrinsic pathway IXa, VIIa, Xa, and – factors released thrombin. from injured • Thrombin tissue specifically cleaves R-G peptide bonds Ann Ny Acad Sci 2001 Mosesson • Why Cascade? 9 10 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Example of isozymes: Isozymes lactate dehydrogenase (LDH) • Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters (i.e. different Km values), or different regulatory properties. – How different? Mammalian lactate dehydrogenase (LDH), which exists – Why different? as five different isozymes, depending on the tetrameric association of two different subunits, A and B: A4, A3B, 11 A2B2, AB3, and B4 12 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture 15.4 Wh at Kin ds of Co va le nt M odifi cati on Regu la tion 2: Cova len t mo difica tion Regulate the Activity of Enzymes? –Catalytic activities of enzymes can also be • Phosphorylation altered by reversible, covalent changes to specific amino acid side chains. – Most prom inent form o f cova lent mo dificat ion – Reversible by protein kinases / phosphoprotein Converter enzyme phosph______ – Targgpet specific of kinase (and p pphosph_____) – Regulating proteins are also a target of regulation •Autophosphorylation….. interconvertible enzymes 13 14 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Protein Kinases Classificatin of Kinases • Target residues on target proteins: – Ser ( ), Thr ( ), and Tyr ( ) • Typically recognize specific amino acid sequences in their targets • BtBut, a ll kinases shthare a common catalyttiic mechanism • Regulation of kinases (usually, intrasteric control) – A regulatory subunit with a pseudosubstrate sequence tha t m im ics the targe t sequence – Inhibitor? What kind? 15 16 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Example of Kinase: PKA Structure of PKA • A conserved core kinase domain of about 260 • Cyclic AMP-dependent protein kinase • Protein kinase A (Green) (also known as protein kinase A, PKA • pseudosubstrate • 150- to 170-kD R2C2 tetramer peptide, RRGA *I • The two R (regulatory) subunits bind cAMP (orange) • R su bun its re lease d (Ac tiva te d) from the C • ATP (red) and two Mn2+ (catalytic) subunits after cAMP binding. ions (yellow) • In other kinases, the regulatory sequence may on the same peptide chain. 17 18 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Phosphorylation is Not the Only EndofPart1End of Part 1 Form of Covalent Modification • Ask yourself….. • Types of Protein chemical modification > 100 – How manyyy ways an enzy me could be • OlOnly a few ofthf these are used dt to regu la tion ! regulated? – reversible conversion Related to the energy state of cell – What is a cascade reaction? Is it any good? – What is an isozyme? Where is an isozyme came from? – What is kinase? What kinds of properties kinases have ? 19 20 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Rlti3AlltiRltiRegulation 3: Allosteric Regulation Regulatory Enzymes Have Certain Exceptional Properties • Action at “another site“ ౦Տፓ࿯ • Most key enzymes in metabolic pathways are • Substrate binding is cooperative regulated in this way! • Kinetics are sigmoid ("S-shaped") • Allosteric enzymes are usually oligomeric • Regulation of allosteric enzyme involved protein conformation change • Regulated by allosteric effectors – usually produced elsewhere in the pathway – may be feed-forward activators or feedback inhibitors 21 22 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Mechanism of allosteric enzymes UdUnders tan dMWCd MWC mo dlStdel: Step 1 •MWCConcerted Model (1965, Monod, • The enzyme exists in only two Wyman & Changeux) : interconvertable states. – The enzyme exists in only two – R State – relaxed form interconvertable states or conformations and – T State – taut form all subunits must be in the same state or conformation: • MllMolecules o fidf mixed con forma ti(hition (having •KNFmodel (Koshland, Nemethy, and subunits of both R and T states) are not Filmer ) allowe d by t his mo de l (symmetry mode l) – Ligand binding triggers a conformation change in a protein 23 24 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Understand MWC model: Step 2 Understand MWC model: Step 3 • Most of the enzyme oligomers will assume the • The R and the T states have different homogenous T state in the absence of bound affinities for substrate. effector molecules • The su bs tra te dissoc ia tion cons tan t for the • If no effector molecule is bound, then the R and T R state is defined as KR (so as KT). states are indicated as: R0 and T0 KR ERS ER+S [ER][S] KR = [ERS] b • Assuming KT>>KR KR/KT = 0 • The equilibrium constant L is assumed to be It means most Su bstrates bind only to R large! 25 26 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Understand MWC model: Step 4 Understand MWC model: Step 5 • Most enzyme in T state • Most substrates bind to R state • Key point is the [R0] and [T0] • 2 ways to increase [R0] 27 28 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Understand MWC model: Step 6 KNF model • Heterotropic effectors • Based on ligand-induced conformation – Molecules that influence the binding of something other than themselves changgyes of enzymes • Homotropic effectors • If the protein is oligomeric, ligand-induced – Ligan ds suc h as S are pos itive homo trop ic conformation changes in one subunit may effectors (homotropic activators) lead to conformation changes in adjacent • SbidiS binding increases the popu ltilation o fRf R, subunits which increases the sites available to S • Explains negative cooperativity – Cooperativity • Also known as sequential model 29 30 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Explanation of KNF model Enzymes Controlled by Both Allosteric Regulation and Covalent Modification (a) A subunit changes its • Use Glycogen phosphorylase (GP) as an conformation after S example! binding (induced fit) • GP cleaves glucose units from nonreducing (b) Binding of S to one subunit may cause the endflds of glycogen other subunit changing its • The product, conformation to (˓* glucose-1-phosphate ȸ ˓ having a greater affinity for S (positive cooperativity) is a readily usable ȸ ˓ havinggy a less affinity for fuel S (negative cooperativity) 31 32 Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Glucose-1-phosphate Glucose-6-phosphate • In muscle glucose-6-phosphate is used to • Glucose-6-phosphate is the real metabolite for produce energy energy production. – You will learn the detail in Chapter 18 • In the liv er it is u ltimately transported to other tissues via the circulatory system • G-1-P can easily be converted to G-6-P by the phosphoglucomutase Hanjia’s Biochemistry Lecture Hanjia’s Biochemistry Lecture Stru ctu re of glycogen phosphory lase Allosteric Regulation of GP • Muscle GP is a homodimer – Each 842 amino acids, ~97 kD – Each subunit contains 1. a pyridoxal phosphate* cofactor, covalently linked as a Schiff base** to Lys680. • Phosphate (Pi) shows strong positive cooperativity. 2. an active site (at the center of the subit)bunit)
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