Terpene Biosynthesis: Modularity Rules

Abstract

Terpenes are the largest class of small molecule natural products on Earth, and the most abundant by mass. Here, we summarize recent developments in elucidating the structure and function of the proteins involved in their biosynthesis. There are 6 main building blocks or modules (α,β,γ,δ,ε and ζ) that make up the structures of these enzymes: the αα and αδ head-to-tail trans-prenyl transferases that produce trans-isoprenoid diphosphates from C5 precursors; the ε head-to-head prenyl transferases that convert these diphosphates into the tri-and tetra-terpene precursors of sterols, hopanoids and carotenoids; the βγ di- and tri-terpene synthases; the ζ head-to-tail cis-prenyl transferases that produce the cis-isoprenoid diphosphates involved in bacterial cell wall biosynthesis, and finally the α, αβ and αβγ terpene synthases that produce plant terpenes, with many of these modular enzymes having originated from ancestral α and β domain proteins. We also review progress in determining the structure and function of the two 4Fe-4S reductases involved in formation of the C5 diphosphates in many bacteria, where again, highly modular structures are found.

Antiinfectives targeting enzymes and the proton motive force

“…This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance. molecular dynamics simulations | clofazimine | bedaquiline | clomiphene | vacquinol T here is a need for new antibiotics, due to the increase in drug resistance (1,2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3,4).…”

“…Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9)(10)(11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1).…”

“…1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent than was SQ109 (2) against M. tuberculosis H37Rv [0.063 vs. 0.25 μg/mL minimal inhibitory concentration (MIC)], and that at least one protonatable nitrogen in the linker was essential for activity.…”

Unique Biosynthesis of Sesquarterpenes (C35Terpenes)

“…31) It has been reported that many terpene cyclases have broad substrate specificities, and that other classes of terpenes have been created in vitro. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] A combination of studies identifying enzymatic products biosynthesized from unusual substrates and the analysis of genome sequences should lead not only to the discovery of additional functions of these enzymes in the organism, but also to the identification of novel natural terpenoids that have functions in their producers.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] These compounds including hormones, vitamins, drugs, flavorings, and pigments, are categorized by number of C 5 isoprene units, as follows: hemi-(C 5 ), 1 unit; mono-(C 10 ), 2 units; sesqui-(C 15 ), 3 units; di-(C 20 ), 4 units; sester-(C 25 ), 5 units; tri-(C 30 ), 6 units; and tetraterpenes (C 40 ), 8 units. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] In contrast, little is known about C 35 terpenes. To the best of my knowledge, only 19 cyclic and eight linear C 35 terpenes have been identified to date, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]…”