The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems

Abstract

Chemical reactions that are named in honor of their true, or at least perceived, discoverers are known as "name reactions". This Review is a collection of biological representatives of named chemical reactions. Emphasis is placed on reaction types and catalytic mechanisms that showcase both the chemical diversity in natural product biosynthesis as well as the parallels with synthetic organic chemistry. An attempt has been made, whenever possible, to describe the enzymatic mechanisms of catalysis within the context of their synthetic counterparts and to discuss the mechanistic hypotheses for those reactions that are currently active areas of investigation. This Review has been categorized by reaction type, for example condensation, nucleophilic addition, reduction and oxidation, substitution, carboxylation, radical-mediated, and rearrangements, which are subdivided by name reactions.

Keywords: biosynthesis; catalysis; enzymes; name reaction; reaction mechanisms.

Figure 1

Aldol condensation and related reactions.

Figure 2

Reaction mechanisms of type I and II aldolases. (a) Fructose 1,6-diphosphate aldolase (type I) and (b) fuculose 1-phosphate aldolase (type II).

Figure 3

Proposed reaction mechanism for porphobilinogen synthase.

Figure 4

The folic acid biosynthetic pathway in bacteria.

Figure 5

Proposed mechanism of serine hydroxymethylase.

Figure 6

Proposed mechanism of 1-deoxy-D-xylulose-5-phosphate reducto-isomerase.

Figure 7

Proposed mechanism of DnmZ.

Figure 8

Kynureninase catalyzes a retro-Claisen reaction.

Figure 9

(a) Type II fatty acid biosynthesis. (b) Mechanisms of Fab-H catalyzed and (c) FabB or FabF-catalyzed decarboxylating Claisen condensations.

Figure 10

Thiolase-catalyzed biosynthetic and degradative reactions.

Figure 11

(a) Type 1 and (b) type II polyketide synthase-catalyzed reactions.

Figure 12

Reaction mechanisms of chalcone and stilbene synthase.

Figure 13

Tetramic acid-containing natural products.

Figure 14

Proposed biosynthesis of (a) tetramic and (b) tetronic acid.

Figure 15

MenB-catalyzed Dieckmann condensation.

Figure 16

BadI-catalyzed reverse Dieckmann condensation involved in the anaerobic degradation of aromatic compounds.

Figure 17

Pictet-Spengler reactions for the synthesis of (a) THIQ and (b) THBC.

Figure 18

(a) Proposed mechanism of the STR-catalyzed reaction. (b) The microbial McbB-catalyzed Pictet-Spengler reaction.

Figure 19

Proposed mechanism of the NCS-catalyzed reaction.

Figure 20

Biosynthetic pathway of the alkaloids in Alangium lamarckii.

Figure 21

Proposed biosynthetic pathway of saframycin A.

Figure 22

(a) Knoevenagel reaction and (b) enzymatic Knoevenagel reactions.

Figure 23

Friedländer quinoline synthesis.

Figure 24

Proposed mechanism for (a) LanC-catalyzed Michael addition and (b) the reaction catalyzed by maleylacetoacetate isomerase.

Figure 25

Proposed mechanism for tryptophan synthase.

Figure 26

Proposed mechanism for cystathionine γ-synthase.

Figure 27

Proposed mechanism for nitroalkane oxidase.

Figure 28

Proposed mechanism for alkyldihydroxyacetone phosphate synthase.

Figure 29

Michael addition and lactonization catalyzed by a branching module.

Figure 30

(a) Morita-Baylis-Hillman reaction. (b) Rauhut-Currier reaction.

Figure 31

Proposed reaction mechanism for thymidylate synthase.

Figure 32

The biosynthetic pathway of spinosyn A.

Figure 33

Proposed mechanisms of the conversion of 8-oxogeranial to iridodial. (a) Rauhut-Currier reaction covalently assisted by a nucleophilic residue occurs first followed by reduction. (b) Reduction occurs priot to Michael reaction.

Figure 34

(a) Mannich reaction. (b) The proposed biosynthetic pathway of hyoscyamine and scopolamine.

Figure 35

Stetter reaction and benzoin condensation.

Figure 36

Proposed mechanism of MenD-catalyzed reaction.

Figure 37

PigD-catalyzed Stetter reactions.

Figure 38

Reaction mechanism of transketolase.

Figure 39

(a) Prins reaction. (b) Proposed reaction mechanism catalyzed by geosmin synthase.

Figure 40

Henry nitroaldol reaction and hydroxylnitrile lyase-catalyzed reversible cyanohydrin formations.

Figure 41

Ugi reaction.

Figure 42

Baeyer-Villiger reaction and Criegee intermediate.

Figure 43

Proposed mechanism of cyclohexanone monooxygenase (CHMO).

Figure 44

(a) Proposed lactonization catalyzed by Hgc3. (b) The GilOII-catalyzed C-C bond cleavage reaction.

Figure 45

The proposed mechanism of BluB-catalyzed reaction.

Figure 46

The proposed mechanism of CcsB-catalyzed carbonate formation.

Figure 47

Proposed biosynthetic pathway for legonmycins.

Figure 48

The proposed biosynthetic pathway of aflatoxin B₁ and mechanisms of key enzymes involved.

Figure 49

The lactonization catalyzed by brassinolide synthase.

Figure 50

Mechanistic proposal for the degradation of toxoflavin.

Figure 51

(a) Prilezhaev reaction. (b) Biological equivalents of peracids. (c) Proposed mechanism and examples of P450 enzyme-catalyzed epoxidation.

Figure 52

Epoxidation reactions catalyzed by flavoproteins, (a) squalene 2,3-epoxidase (b) Af1206095.

Figure 53

(a) Nef reaction. (b) Nef reaction via reductive methods. (c) Nef reaction catalyzed by old yellow enzymes.

Figure 54

(a) Cannizzaro reaction. (b) The conversion of methylglyoxal to lactate catalyzed by glyoxalase I and II.

Figure 55

Bacterial anabolism of phenols.

Figure 56

Birch reduction.

Figure 57

Benzoyl-CoA reductases. (a) Anabolic metabolism of phenols in T. aromatica. (b) BamBC-catalyzed reduction of benzoyl-CoA in G. metallireducens.

Figure 58

Proposed catalytic cycle of hydroxybenzoyl-CoA reductase.

Figure 59

(a) Reactions catalyzed by IspH. (b) Proposed Birch-like reduction mechanism. (c) Proposed organometallic mechanism.

Figure 60

Amadori rearrangement.

Figure 61

(a) The Amadori rearrangement in the proposed catalytic mechanism of GCHI. (b) The natural products which share GCHI-catalyzed reaction in their biosynthesis.

Figure 62

Biosynthesis of thiazole phosphate in Bacillus subtilis.

Figure 63

Proposed mechanism for 2-thiosugar formation in BE-7585A biosynthesis.

Figure 64

(a) Bamberger rearrangement. (b) Proposed pathway for the enzyme-catalyzed biodegradation of nitrobenzene.

Figure 65

Nucleophilic activation of enediynes via Bergman or Myers-Saito cyclizations.

Figure 66

(a) Fries rearrangement and photo-Fries rearrangement. (b) Proposed Fries rearrangement catalyzed by soy bean peroxidise.

Figure 67

(a) Lossen rearrangement. (b) Non-enzymatic Lossen rearrangement in glucosinolate degradation.

Figure 68

Criegee rearrangement.

Figure 69

(a) Catechol intradiol dioxygenase. (b) Catechol extradiol dioxygenase.

Figure 70

Possible mechanism for the cleavage reaction catalyzed by carotenoid cleavage dioxygenase.

Figure 71

(a) Favorskii rearrangement. (b) Biosynthetic pathway of enterocin and proposed mechanism for EncM.

Figure 72

(a) Pinacol rearrangement. (b) General semipinacol rearrangement.

Figure 73

Proposed isotopic labeling patterns in stipitatic acid biosynthesis.

Figure 74

Proposed mechanism of tropolone formation catalyzed by TropC.

Figure 75

Proposed biosynthetic pathway of aurachin A-D.

Figure 76

Proposed reaction mechanisms of AuaG/AuaH-catalyzed prenyl group migration.

Figure 77

Proposed mechanisms for (a) monoterpene and (b) sesquiterpene synthases.

Figure 78

Pericyclic name reactions catalyzed by enzymes.

Figure 79

Transition state of the reaction catalyzed by chorismate mutase.

Figure 80

(a) Proposed lyn biosynthetic pathway. (b) LynF-catalyzed O-prenylation and the spontaneous Claisen rearrangement of the analog of aestuaramide B.

Figure 81

Proposed mechanisms for the reaction catalyzed by DMAT.

Figure 82

Proposed mechanism for TclM-catalyzed aza-[4+2] cycloaddition.

Figure 83

(a) Versipelostatin and the VstJ-catalyzed reaction. (b) Pyrroindomycin and PryE3-catalyzed decalin formation.

Figure 84

Proposed biosynthetic pathway of ikarugamycin.

Figure 85

The [4+2] cycloaddition reaction catalyzed by SpnF may be a step process involving [6+4] cycloaddition reaction followed by Cope rearrangement.

Figure 86

(a) Selected reactions catalyzed by dimethylallyltryptophan synthases. (b) Proposed mechanisms for the reaction catalyzed by dimethylallyltryptophan synthase.

Figure 87

(a) The MIO-based amino acids lyases and mutases. (b) Formation of MIO by post-translational modification.

Figure 88

Proposed mechanisms for HAL-catalyzed reaction.

Figure 89

(a) Kolbe-Schmitt carboxylation reaction. (b) Possible roles of αβγ and δ subunits in the phenylphosphate carboxylation reaction.

Figure 90

(a) The reactions catalyzed by bacterial UbiD/UbiX and fungal Fdc1/Pad1. (b) FMNH₂ prenylation catalyzed by UbiX/Pad1. (c) Proposed mechanism for UbiD/Fdc1-catalyzed reversible decarboxylation.

Figure 91

(a) Grob fragmentation. (b) Proposed mechanism for marneral synthase.

Figure 92

(a) The Hunsdiecker halogenation. (b) A metal-free version of Hunsdiecker reaction. (c) Proposed mechanism for Bmp5-catalyzed decarboxylative bromination.