Recent Advances in Metabolically Engineered Microorganisms for the Production of Aromatic Chemicals Derived From Aromatic Amino Acids

Abstract

Aromatic compounds derived from aromatic amino acids are an important class of diverse chemicals with a wide range of industrial and commercial applications. They are currently produced via petrochemical processes, which are not sustainable and eco-friendly. In the past decades, significant progress has been made in the construction of microbial cell factories capable of effectively converting renewable carbon sources into value-added aromatics. Here, we systematically and comprehensively review the recent advancements in metabolic engineering and synthetic biology in the microbial production of aromatic amino acid derivatives, stilbenes, and benzylisoquinoline alkaloids. The future outlook concerning the engineering of microbial cell factories for the production of aromatic compounds is also discussed.

Keywords: aromatic amino acid derivatives; benzylisoquinoline alkaloids; metabolic engineering; microorganism; stilbenes; strain construction.

Figure 1

Biosynthetic pathway of aromatic amino acids. Black, Escherichia coli genes; Underlined genes, Saccharomyces cerevisiae genes; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; G3P, glyceraldehde-3-phosphate; PEP, phosphoenolpyruvate; Pyr, pyruvate; Ac-CoA, acetyl-CoA; TCA cycle, tricarboxylic acid cycle; Ru5P, ribulose-5-phosphate; X5P, xylulose-5-phosphate; R5P, ribose-5-phosphate; S7P, sedoheptulose-7-phosphate; E4P, D-erythrose 4-phosphate; DAHP, 3-deoxy-D-arabino-heptulosonate-7-phosphate; DHQ, 3-dehydroquinate; DHS, 3-dehydroshikimate; SA; shikimic acid; S3P, shikimate-3-phosphate; EPSP, 5-enolpyruvylshikimate 3-phosphate; PP, phenylpyruvate; 4HPP, 4-hydroxyphenylpyruvate; L-Phe, L-phenylanine; L-Tyr, L-tyrosine; L-Trp, L-tryptophan. ptsHI, phosphocarrier protein HPr and PTS enzyme I genes; galP, galactose, H (+) symporter gene; glk, glucokinase gene; zwf, glucose-6-phosphate dehydrogenase gene; tkt, transketolase 1 gene; tal, transaldolase A gene; ppsA, phosphoenolpyruvate synthase; pykFA, pyruvate kinase I and II genes; aroF/aroG/aroH, 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase genes; aroB, 3-dehydroquinate synthase gene; aroD, 3-dehydroquinate dehydratase gene; aroE, dehydroshikimate reductase gene; aroK/aroL, shikimate kinase genes; aroA, EPSP synthase gene; aroC, chorismate synthase gene; pheA/tyrA, chorismate mutase/prephenate dehydrogenase gene; tyrB, aromatic-amino-acid transaminase gene; trpD/trpE, anthranilate synthase gene; trpC, phosphoribosylanthranilate isomerase gene; trpA, indoleglycerol phosphate aldolase gene; trpB, tryptophan synthase gene; tnaB/mtr, tryptophan: H (+) symporter gene; aroP, aromatic amino acid: H (+) symporter gene; yddG, aromatic amino acid exporter gene; ARO3/ARO4, 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase genes; ARO2, chorismate synthase; ARO7, chorismate mutase gene; TYR1, prephenate dehydrogenase gene; ARO8/ARO9, aromatic acid aminotransferase gene; PHA2, prephenate dehydratase gene; TRP2/TRP3, anthranilate synthase gene; TRP4, anthranilate phosphoribosyl transferase gene; TRP1, N-(5'-phosphoribosyl)-anthranilate isomerase gene; TRP3, indole-3-glycerol phosphate synthase gene; TRP5, tryptophan synthetase gene.

Figure 2

Biosynthesis of L-phenylalanine derivatives. ldhA, lactate dehydrogenase gene; ipdC/ARO10/kdc, phenylpyruvate decarboxylase gene; yahK/ADH6/yigB/adh, aldehyde reductase; feaB, phenylacetaldehyde dehydrogenase gene; L-AAD, L-amino acid deaminase gene; ARO8: PAL1, phenylalanine ammonia lyase gene; FDC1, ferulic acid decarboxylase 1 gene; styAB, styrene monooxygenase genes; styC, styrene oxide isomerase gene; hmaS, S-mandelate synthesis gene; hmo, l-4-hydroxymandelate oxidase gene; hpgT, l-4-hydroxyphenylglycine transaminase gene; pglE, phenylglycine aminotransferase; hpgAT, D-(4-Hydroxy)phenylglycine aminotransferase gene; dmd, D-mandelate dehydrogenase gene.

Figure 3

Biosynthesis of L-tyrosine derivatives. 4HPLA, 4-hydroxyphenyllactic acid; 4HPAAL, 4-hydroxyphenylacetaldehyde; 4HPAA, 4-hydroxyphenylacetic acid; ldhA/d-ldh, D-lactate dehydrogenase gene; hdhA, 2-hydroxyacid dehydrogenase gene; hpaBC, p-hydroxyphenylacetate 3-hydroxylase genes; ipdC/ARO10/kdc, phenylpyruvate decarboxylase gene; yahK/ADH6, alcohol dehydrogenase gene; UGT, uridine diphosphate dependent glycosyltransferase gene; aas, aromatic aldehyde synthase gene; RAS, rosmarinic acid synthase gene; tyr, tyrosinase gene; tdc, tyrosine decarboxylase gene; tyo/tynA, tyramine oxidase gene; tal, tyrosine ammonia lyase gene; dodc, L-DOPA decarboxylase; pdc, p-coumaric acid decarboxylase gene; 4cl, 4-coumaroyl-coenzyme A ligases gene; sam5, 4-coumarate hydroxylase gene; com, caffeic acid methyltransferase gene; HQT, hydroxycinnamate-CoA quinate transferase gene; HST, hydroxycinnamate-CoA shikimate transferase gene; pad, phenolic acid decarboxylase gene; CURS, curcumin synthase gene.

Figure 4

Biosynthesis of L-tryptophan derivatives. HCBT, anthranilate N-hydroxycinnamoyl/benzoyltransferase gene; salABCD, salicylate 5-hydroxylase gene; AAAH, aromatic amino acid hydroxylase gene; TDC, tryptophan decarboxylase gene; T5H, tryptamine 5-hydroxylase gene; tnaA, tryptophanase gene; fmo, flavin-containing monooxygenase gene; HCTT, hydroxycinnamoyl-CoA:tryptamine N-hydroxycinnamoyl transferase gene; vioA, tryptophan 2-monooxygenase/L-tryptophan oxidase gene; vioB, 2-imino-3-(indol-3-yl)propanoate dimerase gene; vioE, violacein biosynthesis protein gene; vioC, violacein synthase gene; vioD, protodeoxyviolaceinate monooxygenase gene.

Figure 5

Biosynthesis of stilbenes, benzylisoquinoline alkaloids. Black, microorganism genes; Boxed genes, mammalian (Rattus norvegicus/ Bombyx mori) genes; Underlinded, plant genes; Boxed and underlined genes, cytochrome P450 genes; Ma-CoA, malonyl-CoA; (S)-NorLaud, (S)-norlaudanosoline; (S)-THP, (S)-tetrahydropapaveroline; (S)-NorRet, (S)-norreticuline; BH₄, tetrahydrobiopterin; pal, phenylalanine ammonia lyase gene; 4cl, 4-coumaroyl-coenzyme A ligase gene; sts, stilbene synthase gene; c4h, 4-cinnamic acid hydroxylase gene; sam5, 4-coumarate hydroxylase gene; c3h, p-coumarate 3-hydroxylase gene; romt, resveratrol O-methyltransferase; tyr/tyrH, tyrosinase gene; DHPAAS, 3,4-dihydroxyphenylacetaldehyde synthase gene; dodc, DOPA decarboxylase gene; tydc, tyrosine decarboxylase gene; mao, monoamine oxidase gene; NCS, norcoclaurine synthase gene; 6OMT, norcoclaurine 6-O-methyltransferase gene; CNMT, coclaurine-N-methyltransferase gene; 4'-OMT, 3'-hydroxy-N-methylcoclaurine-4'-O-methyltransferase gene; CYP80G2, corytuberine synthase gene; BBE, berberine bridge enzyme gene; GTPCHI, GTP cyclohydrolase I gene; PTPS, 6-pyruvoyl-tetrahydropterin synthase gene; SepR, sepiapterin reductase gene; PCD, pterin-4α-carbinolamine dehydratase gene; QDHPR, quinonoid dihydropteridine reductase gene; S9OMT, scoulerine 9-O-methyltransferase gene; CAS, canadine synthase gene; CPR, cytochrome P450 reductase gene; TNMT, tetrahydroprotoberberine cis-N-methyltransferase gene; CYP82Y1, 1-hydroxy-N-methylcanadine synthase gene; CYP82X2, 1- hydroxy-N-methylcanadine 13-hydroxylase gene; AT1, 1,13-dihydroxy-N-methylcandine 13-O-acetyltransferase gene; CYP82X1, 1-hydroxy-13-O-acetyl-N-methylcanadine 8-hydroxylase gene; CXE1, 3-O-acetylpapaveroxine carboxylesterase gene; SDR1, short-chain dehydrogenase/reductase gene; N4'-OMT, narcotoline-4′-O-methyltransferase gene; CFS, cheilanthifoline synthase gene; STS, stylopine synthase gene; TNMT, tetrahydroprotoberberine N-methyltransferase gene; MSH, cis-N-methylstylopine 14-hydroxylase gene; P6H, protopine 6-hydroxylase gene; DBOX, dihydrobenzophenanthridine oxidase gene; STOX, (S)-tetrahydroprotoberberine oxidase gene; STORR, (S)-reticuline isomerase gene; SAS, salutaridine synthase gene; SAR, salutaridinol reductase gene; SAT, salutaridinol acetyltransferase gene; CODM, codeine-O-demethylase gene; T6OMT, thebaine 6-O-demethylase gene; COR, codeinone reductase gene; morA, morphine dehydrogenase; morB, morphine reductase.