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Abstract
Aromatic amino acid metabolism in yeast is an important source of secondary compounds that influence the aroma and
flavour of alcoholic beverages and foods. Examples are the higher alcohol 2-phenylethanol, and its acetate ester, 2-
phenylethyl acetate, which impart desirable floral aromas in wine, beer and baker’s products. Beyond this wellknown
influence on the organoleptic properties of alcoholic beverages and foods, there is a growing interest in understanding and
modulating yeast aromatic amino acid metabolism. The tryptophan derivatives melatonin and serotonin have bioactive
properties and exert positive effects on human health, and aromatic amino acids are also the precursors of products of
industrial interest, such as nutraceuticals, fragrances, and opium-derived drugs. This mini-review presents current knowledge
on the formation of compounds from aromatic amino acids by Saccharomyces cerevisiae, from genetic and environmental
influences on their flavour impacts in alcoholic beverages to their potential as bioactive compounds, and the use of yeast as
microbial factories for the production of com-
mercially relevant aromatic compounds.
formation of these aromatic compounds. Steyer et al. (2012) acids. Endogenous aromatic amino acid anabolic and catabolic
pathways are indicated with full black arrows; enzymes and
identified allelic variations in ABZ1 affecting the production
metabolites naturally produced by yeast are shown in black font.
of 2-PE and 2-PEA during fermentation. Abz1p is involved Overexpression of heterologous enzymes (blue arrows) or pathways
in the synthesis of paminobenzoic acid from chorismate, the (thick blue arrows) and metabolites derived from these pathways are
last common intermediate of aromatic amino acid indicated in blue font. Dotted red lines indicate the major allosteric
checkpoints in the pathway: inhibition of Aro3p by L-phe and Aro4p
biosynthesis (Fig. 2). Recently, two natural alleles that
and Aro7p by L-tyr. Overexpression of modified Aro4pK229L and
modulate the formation of both 2-PEA and 2-PE in Aro7pG141S results in tyrosine-insensitive enzymes. In addition, Aro7p
industrial strains were identified: a dominant allele of FAS2, is activated by L-trp (green dotted lines). The biosynthesis of aromatic
which encodes the alpha subunit of the fatty acid synthetase amino acids starts with the condensation of two glucose-derived
Appl Microbiol Biotechnol
metabolites erythrose-4phosphate (E4P) and phosphoenolpyruvate step conversion from L-tyr or a 2-step conversion from L-phe. p-
(PEP) and followed by a series of enzymatic reactions which lead to coumaric acid is the precursor of a series of biotechnological important
the formation of chorismate (shikimate pathway). Then, chorismate compounds (resveratrol, anthocyanins and raspberry ketone). L-tyr and
can enter the L-trp biosynthesis branch or converted by Aro7p into 4-hydroxyphenylacetaldehyde (4-HPAA) are precursors of
prephenate, the last common precursor for L-tyr/phe biosynthesis. benzylisoquinoline alkaloids, while dehydroshikimate (DHS) is the
Tryptophol, tryptophan and cell density upregulate the expression of precursor of vanillin and muconic acid. DAHP, 3-deoxy-D-
ARO9 and ARO10, which is dependent on the transcription factor arabinoheptulosonate-7-phosphate; 4HPP, 4-hydroxyphenylpyruvate
Aro80p (green lines). The formation of p-coumaric acid follows a 1-
metabolism to enhance the flux of carbon towards the breeding methods, such as hybridization or mutagenesis and
aromatic amino acid pathway (Cordente et al. 2018; Koseki selection, and more recently to the use of selected cultures
et al. 2004; Oba et al. 2005). Key enzymes of the aromatic of non-Saccharomyces yeast or adaptive evolution
biosynthetic pathway are subject to feedback inhibition by techniques.
terminal amino acidproducts (Braus1991) (Fig. 2),and the
use of toxic amino acid analogues allows the selection of
cells with decreased feedback inhibition of amino acid Yeast as cell factories for the production of
synthesis, thereby causing amino acid overproduction and aromatic compounds
metabolic overflow to corresponding higher alcohols. In
particular, increased production of isoamyl alcohol, tyrosol The aromatic amino acid biosynthetic pathway is a source
and 2-PE has been achieved by selecting yeast mutants with of many commercially relevant chemicals, with diverse
resistance to toxic fluorinated amino acid analogues of L- industrial applications, as reviewed by Suastegui and Shao
leucine (Oba et al. 2005), L-tyr (Koseki et al. 2004) and L- (2016). Some ofthese chemicals include flavour compounds
phe (Akita et al. 1990; Cordente et al. 2018; Dueñas- (vanillin, raspberry ketone and 2-PE), pain-management
Sanchez et al. 2014), respectively. Two fluorinated pharmaceuticals (benzylisoquinoline alkaloids) or
diastereomers of phe have been widely used, p-fluoro-DL- nutraceuticals (resveratrol), and S. cerevisiae has been
phenylalanine (PFP) and o-fluoroDL-phenylalanine (OFP), widely used as a microbial factory for the production of
which selectively target two different enzymatic activities of these compounds. Metabolic engineering of yeast generally
the pathway. PFP-resistant mutants usually present involves the enhancement of the flux of carbon into the
mutations in TYR1, accumulate both 2-PE and tryptophol, aromatic amino acid biosynthetic pathway, together with the
and produce less L-tyr (Akita et al. 1990; Cordente et al. introduction of the heterologous biosynthetic pathway
2018; Fukuda et al. 1991a). OFP-resistant strains also needed for the production of the specific compound being
accumulate 2-PE, and these usually present mutations in targeted.
ARO4, which releases the enzyme from feedback inhibition The most common strategies to optimise flux into the
by L-tyr (Cordente et al. 2018; Fukuda et al. 1991b). Strains aromatic amino acid pathway include the following: (a)
obtained by these non-GM methods have the potential to be deregulation of key allosteric checkpoints in amino acid
used by the beverage and food industry. biosynthesis by overexpressing mutant versions of ARO4
Even though the use of modern breeding technologies and/or ARO7, which are insensitive to L-tyr levels; (b)
involving genetic engineering of the host organism, such as removing competing pathways by deleting key enzymes of
selfcloning, or more recently CRISPR/Cas9, has the the Ehrlich pathway; (c) overexpressing mutant versions of
potential to revolutionise the generation of industrial strains ARO1 to stop the conversion of intermediates in the
with improved characteristics, currently, there are social, shikimate pathway; and (d) increasing the availability of the
ethical and legislative barriers preventing the use of these main carbon precursor of the aromatic pathway, erythrose-
techniques in the food and beverage sectors. Even though in 4-phosphate (Fig. 2).
countries like Japan, self-cloned yeast strains are not The L-phe/L-tyr pathway has been modified for the de
considered genetically modified organisms, and several novo production of the benzylisoquinoline alkaloids
examples of these strains can be found in the literature thebaine and hydrocodone (Galanie et al. 2015), the
(Ikeda et al. 2018; Kitagaki and Kitamoto 2013), these antioxidant resveratrol (Li et al. 2015), the plant pigment
strains are rarely used in industrial sake brewing (Negoro et anthocyanins (Levisson et al. 2018), and the flavouring
al. 2016). It is uncertain whether in the futurethe use agent raspberry ketone (Lee et al. 2016). Salidroside, a
ofgenetic engineeredstrains inthe beverageand food sectors plant-derived glucoside of tyrosol with diverse biological
would be more acceptable by the wider public. In the properties, has been synthesised to high titers in yeast by
meantime, the development of industrial yeast strains with optimising the endogenous L-tyr biosynthetic pathway and
improved characteristics is restricted to more traditional heterologous expression of plant glucosyltransferases (Jiang
Appl Microbiol Biotechnol
et al. 2018). The rose-like aroma compound 2-PE is an Although, in general, these nonSaccharomyces species
important fragrance ingredient in the food, cosmetic and synthesise lower amounts of aromatic higher alcohols than
perfume industries, as well as a preservative and a S. cerevisiae, when used in coinoculation with S. cerevisiae,
disinfectant—its market is expected to reach US$700 they result in wines with comparable and even higher
million by 2019 (Pandal 2014). Yeast bioconversion of a amounts of 2-PE than those obtained with S. cerevisiae alone
fermentation media with L-phe as the sole nitrogen source (Azzolini et al. 2015; Barbosa et al. 2015). Co-inoculation
has proved a promising alternative to the synthesis of 2-PE of non-Saccharomyces yeasts alongside S. cerevisiae is also
using chemical methods. This, in combination with different an emerging trend to enhance beer flavour, for example T.
in situ extraction methods, to counter the toxicity of delbrueckii was shown to increase formation of several
2PEtoyeast,hasyieldedtitersof16g/L(Okuniewskaetal.2017). higher alcohols and some acetate esters (Canonico et al.
By engineering the L-trp branch in yeast using 2017).
heterologous enzymes, it was also possible to produce high The potential of non-conventional yeast to produce
levels of the mammalian hormone melatonin (Germann et aromatic compounds was systematically analysed amongst
al. 2016), which is naturally produced by S. cerevisiae in a collection of 143 different species (Gamero et al. 2016).
μg/L concentrations. The diversity of aroma profiles was significant, and,
interestingly, some of the strains were able to produce higher
concentrations of aroma compounds than reference
Harnessing other yeast species for aroma Saccharomyces strains, such as strains of the species
production Starmera caribaea (isolated from cacti) or H. guilliermondii
(isolated from grapes). Notably, those species, together with
Although the pathways leading to the formation of flavour
H. vineae, produced significantly more 2PEA than S.
compounds have been mainly studied in S. cerevisiae,
cerevisiae (Gamero et al. 2016; Lleixa et al. 2016). These
several studies indicate that the Ehrlich pathway is
results suggest that the pathways involved in the formation
conserved across a range of yeast genera and species
of these flavour compounds, such as the Ehrlich pathway, or
(Gamero et al. 2016; González et al. 2018; Stribny et al.
the specific enzymes responsible for ester synthesis, are also
2015).
present in non-conventional yeasts. However, the regulation
Global volatile compound analyses performed on other
of their expression, the functionality of the enzymes and
Saccharomyces species with interesting oenological
even the number of gene copies in the genome are different
properties revealed that Saccharomyces kudriavzevii
in nonconventional yeasts compared to Saccharomyces
produced relatively high concentrations of higher alcohols,
species (Giorello et al. 2019; Seixas et al. 2019).
whereas Saccharomyces uvarum excelled in the production
of acetate esters (Stribny et al. 2015). Differences found
amongst the Saccharomyces species during aroma formation Future directions
may be due, to some extent, to different enzymatic activities
and properties of the alcohol acetyltransferases Atf1p and While much progress has been made in understanding yeast
Atf2p and the decarboxylase Aro10p (Stribny et al. 2016a, metabolism of amino acids, much work remains. Until
b). These species typically struggle to ferment to completion recently, the main interest in amino acid metabolism was
in high-sugar starting materials, such as grape must, but their driven by the importance of the amino acid-derived higher
potential impacts can be harnessed through interspecies alcohols and acetate esters, in the aroma and flavour of
hybridisation with robust S. cerevisiae strains. For example, alcoholic beverages and foods. One of the limitations when
newly generated interspecific wine yeast hybrids introduce studying flavour compound production is that it represents a
flavour and aroma diversity to wines, particularly non-selectable and polygenic trait, which has limited studies
Saccharomyces mikatae/S. cerevisiae hybrids that produce concerning the genetic mechanisms responsible for the
elevated concentrations of both 2-PE and 2-PEA (Bellon et variations observed between yeast strains in the production
al. 2013). of these compounds. It is not surprising that until recently
In addition, several non-Saccharomyces wine yeast the breeding of S. cerevisiae strains with altered formation
species are of increasing oenological interest, such as of aromatic compounds relied in techniques that do not
Hanseniaspora uvarum, Hanseniaspora vineae, require a previous knowledge of the genetic determinants
Metschnikowia pulcherrima, Zygosaccharomyces bailii, responsible for their formation, such as the use of toxic
Hanseniaspora guilliermondii, or Torulaspora delbrueckii.
Appl Microbiol Biotechnol
analogues of amino acids to isolate strains with altered Little research has been performed in studying the
amino acid metabolism. conditions leading to the formation of the off-flavours
The development of low-cost and powerful sequencing indoleand2-
technologies has allowed the use of QTL mapping strategies aminoacetophenoneinwine.Similarly,thepotential role in
to identify novel alleles involved in the formation of bitterness of tyrosol, and of tryptophol and its sulfonated
aromatic compounds by yeast, such as TOR1, FAS2 or ABZ1. derivative, has not been studied in detail.
Typically performed by genetic crossing between two parent Even for the Ehrlich pathway, little is known about the
strains, a limitation of QTL can be its specificity to the formation of the higher alcohol methionol from the
strains involved. Treusch et al. (2015) utilised a round-robin sulphurcontaining amino acid methionine. Many similarities
approach with 12 strains to study signalling pathway-related exist between the catabolism of methionine and those of the
phenotypes in S. cerevisiae, enabling the identification of aromatic amino acids, and Aro8p seems to be crucial in
important variants across the genetic and phenotypic modulating the formation of both methionol and the
diversity of the species. Similarly, genome-wide association undesirable sulphur compound methanethiol (Deed et al.
applied to a large collection of sequenced and phenotyped 2019). Therefore, it might be possible to modulate the
strains revealed that copy-number variants were an formation of some of these volatile sulphur compounds by
important driver of certain traits (Peter et al. 2018). further studying aromatic amino acid metabolism.
Approaches with such breadth would likely provide great In conclusion, from just a few amino acids, S. cerevisiae
insight into aromatic compound production; however, a can derive a range of aromatic products that enhance
major bottleneck remains the ability to measure the fermented beverage flavour, and others that have various
metabolite of interest for such large populations. Some of industrial or health applications. Further research into the
the compounds derived from aromatic environmental and genetic factors that determine levels of
aminoacids,suchasmelatonin,serotoninorindole,areproduce their production and research that harnesses bioconversion
d in low concentrations and require expensive and complex potential of non-Saccharomyces yeasts, whether in their
analytical techniques for their quantification; and there is a own right or as DNA donors for engineered strains, will
limitation in the ability to use high throughput methods for enhance our ability to make flavourful beverages and
their measurement, which might be necessary when develop new industrial processes.
screening progeny from QTL and/or yeast libraries. Acknowledgements The Australian Wine Research Institute (AWRI),
Due to the growing interest in S. cerevisiae as a microbial a member of the Wine Innovation Cluster in Adelaide, is supported by
Australia’s grapegrowers and winemakers through their investment
factory for the production of aromatic compounds with body Wine Australia, with matching funds from the Australian
industrial applications, new and more powerful methods are Government. GB and MJT thank the Ministry of Economy, Industry
being developed to quantify these compounds reliably. and
Recently, a fast HPLC-UV method has been developed to Competitiveness, Spain (Project AGL2016-77505-C3-3-R), for
financial support. CC is supported by funds from the New Zealand
measure more than 20 metabolites of the shikimate/Ehrlich
Winegrowers, the Oregon Wine Board and the Agricultural Research
pathways at low levels (Lai et al. 2017). In addition, Foundation.
melatonin-responsive biosensor strains have been
developed, which could be expanded to detect other related
Compliance with ethical standards
compounds (Shaw et al. 2018). Finally, laserenabled
ambient ionisation mass spectrometry techniques could be Competing interests The authors declare that they have no conflicts of
used for rapid yeast library evaluation of aromatic interest.
metabolites directly from colonies on agar plates, and
without any extraction or sample preparation (Fang and Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Dorrestein 2014).
Beyond the well-studied products of the Ehrlich pathway,
in yeast and within the fermented beverage context, there is
a lack of research concerning aromatic amino acid References
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