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Enzymatic Redox Chemistry 155 Haem-dependent oxygenases M. Akhtar & J.N. Wright (1991) A uniWed mechanistic view of oxidative reactions catalysed by P 450 and related iron-containing enzymes. Nat. Prod. Reports, 8, 527–52. M. Newcomb & P.H. Toy (2000) Hypersensitive radical probes and the mechanisms of cytochrome P450-catalysed hydroxylation reactions. Acc. Chem. Res., 33, 449–55. M. Sono, M.P. Roach, E.D. Coulter & J.H. Dawson (1996) Heme-containing oxygenases. Chem. Rev., 96, 2841–88. Non-haem iron-dependent oxygenases G.J. Cardinale & S. Udenfriend (1974) Prolyl hydroxylase. Adv. Enzymol., 41, 245-300. A.L. Feig & S.J. Lippard (1994) Reactions of non-heme iron (II) centers with dioxygen in biology and chemistry. Chem. Rev., 94, 759–805. K.I. Kivirikko, R. Myllyla & T. Pihlajaniemi (1989) Protein hydroxylation: prolyl 4-hydroxylase, an enzyme with four cosubstrates and a multifunctional subunit. FASEB J., 3, 1609–17. L. Que Jr & R.Y.N. Ho (1996) Dioxygen activation by enzymes with mononuclear nonheme iron active sites. Chem. Rev., 96, 2607–24. J. Sanvoisin, G.J. Langley & T.D.H. Bugg (1995) Mechanism of extradiol catechol dioxygenases: evidence for a lactone intermediate in the 2,3-dihydroxyphenylpropionate 1,2-dioxygenase reaction. J. Am. Chem. Soc., 117, 7836–7. T.D.H. Bugg (2003) Dioxygenase enzymes: catalytic mechanisms and chemical models. Tetrahedron, 59, 7075–7101.
7 Enzymatic Carbon–Carbon Bond Formation 7.1 Introduction The formation of carbon–carbon bonds is central to biosynthesis, which is the assembly of carbon-based compounds within living cells. Most of these compounds are primary metabolites – molecules such as amino acids, carbohydrates and nucleic acids which are necessary to support life. Many organisms also produce secondary metabolites – molecules whose presence is not essential for the survival of the cell, but which often have other biological properties such as defence against micro-organisms or communication with other organisms. In this chapter we shall analyse the types of enzymatic reactions used in the assembly of the carbon skeletons of primary and secondary metabolites, and also carbon–carbon cleavage reactions involved in their degradation. A carbon–carbon bond consists of a pair of electrons contained within a Wlled molecular orbital. Formation of a carbon–carbon bond can be achieved either by donation of a pair of electrons from one carbon atom to an empty orbital on another carbon atom, or by the combination of two single electron species. Examples of these processes are illustrated in Figure 7.1, involving: (1) nucleophilic attack of a carbanion onto an electron-accepting carbonyl group; (2) electrophilic attack of a carbocation onto an electron-rich alkene; (3) recombination of two phenoxy radicals. We shall meet examples of each of these types of carbon–carbon formation reactions in this chapter. One general point to note is that carbanions and carbocations are highenergy species which can usually only be generated under strenuous reaction conditions in organic chemistry. How then are they generated by enzymes that work at neutral pH with relatively weak acidic and basic groups The answer is that carbanion and carbocation intermediates in enzyme-catalysed reactions must be highly stabilised, either by neighbouring groups in the substrate molecule, or by the enzyme active site, using the type of enzyme–substrate interactions mentioned in Section 2.7. This stabilisation will be explained where possible in the following examples; however, in some cases the means by which high-energy intermediates are stabilised is not fully understood. 156
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Introduction to Enzyme and Coenzyme
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Introduction to Enzyme and Coenzyme
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Contents Preface Representation of
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Contents vii 8 Enzymatic Addition/E
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Representation of Protein Three-Dim
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2 Chapter 1 H 2 N O NH 2 + H 2 O Ja
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4 Chapter 1 Table 1.1 The vitamins.
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6 Chapter 1 has very diVerent biolo
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2 All Enzymes are Proteins 2.1 Intr
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10 Chapter 2 (Gln). There are three
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12 Chapter 2 AAA Lys ACA Thr AGA Ar
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14 Chapter 2 H N O H N O Figure 2.8
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16 Chapter 2 (a) (b) Figure 2.12 St
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18 Chapter 2 Figure 2.14 Structure
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20 Chapter 2 (a) X Y Enzyme + Subst
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22 Chapter 2 maintaining protein te
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24 Chapter 2 surface glycoprotein g
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26 Chapter 2 O-linked glycosylation
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28 Chapter 2 Metalloproteins I. Ber
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30 Chapter 3 O N H R CO 2 H acylase
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32 Chapter 3 (a) Free energy uncata
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34 Chapter 3 Ester k rel Effective
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36 Chapter 3 3.4 The importance of
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38 Chapter 3 pKa Tyrosine CH 2 O H
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40 Chapter 3 glycoside hydrolysis (
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42 Chapter 3 O O Glu 143 O − R H
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44 Chapter 3 the hydroxyl groups of
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46 Chapter 3 E + S E + S ES' ES ‘
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48 Chapter 3 Examination of protein
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50 Chapter 3 (Note: Similar results
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52 Chapter 4 (1) Direct UV (2) Radi
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54 Chapter 4 Figure 4.3 PuriWcation
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56 Chapter 4 The two kinetic consta
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58 Chapter 4 Lineweaver−Burk Plot
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60 Chapter 4 E + S K i EI+ I ES E +
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62 Chapter 4 (2) by treatment with
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64 Chapter 4 In general the stereoc
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H D T CO 2 H CO − 2 T HO D H −
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68 Chapter 4 4.5 The existence of i
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70 Chapter 4 18O 18O 18 O O P O −
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72 Chapter 4 If a reaction involves
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74 Chapter 4 O D H ketosteroid isom
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76 Chapter 4 Table 4.3 Group speciW
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78 Chapter 4 [S] (mM) Rate of produ
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80 Chapter 4 Enzyme kinetics I.H. S
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82 Chapter 5 O = C NHR peptidase H
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84 Chapter 5 non-speciWc protease c
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86 Chapter 5 His 57 His 57 Asp 102
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88 Chapter 5 Other serine proteases
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90 Chapter 5 Figure 5.8 Structure o
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92 Chapter 5 now predominate Perhap
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OH R O Zn 2+ O O O Ph Glu 270 H 2 N
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96 Chapter 5 CASE STUDY: HIV-1 prot
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98 Chapter 5 HO Transition state pe
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100 Chapter 5 The aminoacyl group o
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102 Chapter 5 5.5 Enzymatic phospho
Page 115 and 116: 104 Chapter 5 Figure 5.29 Structure
Page 119 and 120: 108 Chapter 5 Adenosine 5 0 -tripho
Page 121 and 122: 110 Chapter 5 functional group. Gly
Page 123 and 124: 112 Chapter 5 CH 2 OH O RO HO OH O
Page 125 and 126: 114 Chapter 5 to these atoms that t
Page 127 and 128: 116 Chapter 5 Problems (1) Using pa
Page 129 and 130: 118 Chapter 5 (6) Retaining glycosi
Page 131 and 132: 120 Chapter 5 J.R. Knowles (1980) E
Page 133 and 134: 122 Chapter 6 +1.0 Redox potential
Page 135 and 136: Table 6.1 Classes of redox enzymes.
Page 137 and 138: 126 Chapter 6 An important point is
Page 139 and 140: 128 Chapter 6 O H − OH − O OH H
Page 141 and 142: 130 Chapter 6 one-electron transfer
Page 143 and 144: 132 Chapter 6 (a) R N H + N O R N H
Page 145 and 146: 134 Chapter 6 Inactivation by trany
Page 149 and 150: 138 Chapter 6 (a) (b) Figure 6.23 S
Page 151 and 152: 140 Chapter 6 glutathione called tr
Page 153 and 154: 142 Chapter 6 neither has a stable
Page 155 and 156: 144 Chapter 6 of the haem cofactor
Page 157 and 158: 146 Chapter 6 Figure 6.33 Active si
Page 159 and 160: 148 Chapter 6 HO H N N O O H N prol
Page 161 and 162: 150 Chapter 6 R R R O 2 , Fe 2+ O O
Page 163 and 164: 152 Chapter 6 CoA. Explain these re
Page 165: 154 Chapter 6 NADH models O. Almars
Page 169 and 170: 158 Chapter 7 O H − OH O − O H
Page 173 and 174: 162 Chapter 7 Figure 7.6 Active sit
Page 175 and 176: 164 Chapter 7 7.3 Claisen enzymes I
Page 177 and 178: 166 Chapter 7 CoAS O EnzB − H D T
Page 179 and 180: 168 Chapter 7 onto the acetyl-thioe
Page 181 and 182: 170 Chapter 7 In the case of erythr
Page 183 and 184: 172 Chapter 7 O HO O − O ATP ADP
Page 185 and 186: 174 Chapter 7 CO 2 − vitamin K-de
Page 187 and 188: 176 Chapter 7 7.8 Thiamine pyrophos
Page 189 and 190: 178 Chapter 7 HN N + N H NH S O OPP
Page 191 and 192: 180 Chapter 7 O OH OH camphor geran
Page 193 and 194: 182 Chapter 7 CH 3 * OPP (−)pinen
Page 197 and 198: 186 Chapter 7 C C C C C O OCH 3 C H
Page 199 and 200: 188 Chapter 7 AcO HO HO NHAc O OH +
Page 201 and 202: 190 Chapter 7 (9) Usnic acid is a n
Page 203 and 204: 192 Chapter 7 Radical couplings W.M
Page 205 and 206: 194 Chapter 8 C-O cleavage H E1 H C
Page 207 and 208: 196 Chapter 8 leads to the formatio
Page 209 and 210: 198 Chapter 8 aconitase citrate cis
Page 211 and 212: 200 Chapter 8 *H R H H CO 2 − NH
Page 213 and 214: 202 Chapter 8 EnzB − 2 H − O 2
Page 215 and 216: 204 Chapter 8 involves no change in
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206 Chapter 8 Glyphosate H H N CO
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208 Chapter 8 (5) Chorismic acid (s
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9 Enzymatic Transformations of Amin
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CO − − 2 CO 2 H H CO 2 − N +
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214 Chapter 9 - BEnz CO − 2 Cl H
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216 Chapter 9 Arg 292 Arg 292 Lys 2
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218 Chapter 9 Arg 292 Asp 292 HN H
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220 Chapter 9 S − B 1 Enz H − C
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222 Chapter 9 9.6 N-Pyruvoyl-depend
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224 Chapter 9 The biosyntheses of n
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226 Chapter 9 Further reading Gener
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228 Chapter 10 B 1 - H + NH 3 CO
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230 Chapter 10 ‘low-barrier’ +
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232 Chapter 10 H S C 6 H 13 HN His
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234 Chapter 10 O H NH 3 CO 2 − CO
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236 Chapter 10 sub-units. Each sub-
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238 Chapter 10 Further reading Gene
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11 Radicals in Enzyme Catalysis 11.
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242 Chapter 11 CH 2 Co III Ad H OH
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244 Chapter 11 − O 2 C − O CO
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246 Chapter 11 H N H O 734 H N H PF
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248 Chapter 11 H H* + H + H 3 N CO
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250 Chapter 11 O HN NH + H 3 N H 3
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252 Chapter 11 cofactor is involved
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254 Chapter 11 Protein Radicals J.
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256 Chapter 12 self-splicing reacti
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258 Chapter 12 Figure 12.2 Structur
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260 Chapter 12 antigen combining si
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262 Chapter 12 R O OR' OH − R O
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264 Chapter 12 CO 2 − − O 2 C O
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266 Chapter 12 (1) Selective substr
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268 Chapter 12 HO O HO OH HO OH O O
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270 Chapter 12 Problems (1) How rev
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Appendix 1: Cahn-Ingold-Prelog Rule
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Appendix 2: Amino Acid Abbreviation
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276 Appendix 3 Preparation of orang
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278 Appendix 4 (2) Intramolecular a
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280 Appendix 4 from water at a-posi
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282 Appendix 4 Chapter 8 (1) Treat
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284 Appendix 4 (b) Formation of rad
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286 Index b-hydroxydecanoyl thioest
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288 Index glycosylation 26-7 glysop
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290 Index phenylalanine ammonia lya
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292 Index transition states 31-2 an
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