GENE EXPRESSION & METABOLISM
Regulation of Amino Acid, Nucleotide, and
Phosphate Metabolism in Saccharomyces cerevisiae
Per O. Ljungdahl*,1and Bertrand Daignan-Fornier†,1
*Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden, and†Université de Bordeaux, Institut de Biochimie et Génétique
Cellulaires, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5095, F-33077 Bordeaux Cedex, France
ABSTRACT Ever since the beginning of biochemical analysis, yeast has been a pioneering model for studying the regulation of
eukaryotic metabolism. During the last three decades, the combination of powerful yeast genetics and genome-wide approaches has
led to a more integrated view of metabolic regulation. Multiple layers of regulation, from suprapathway control to individual gene
responses, have been discovered. Constitutive and dedicated systems that are critical in sensing of the intra- and extracellular
environment have been identified, and there is a growing awareness of their involvement in the highly regulated intracellular
compartmentalization of proteins and metabolites. This review focuses on recent developments in the field of amino acid, nucleotide,
and phosphate metabolism and provides illustrative examples of how yeast cells combine a variety of mechanisms to achieve
coordinated regulation of multiple metabolic pathways. Importantly, common schemes have emerged, which reveal mechanisms
conserved among various pathways, such as those involved in metabolite sensing and transcriptional regulation by noncoding RNAs or
by metabolic intermediates. Thanks to the remarkable sophistication offered by the yeast experimental system, a picture of the intimate
connections between the metabolomic and the transcriptome is becoming clear.
TABLE OF CONTENTS
Nitrogen source utilization: the flow of nitrogen to amino acids, purines, and pyrimidines
Nitrogen source: quality of amino acids
Biosynthesis of amino acids
Nitrogen-regulated gene expression
Target of rapamycin (TOR) signaling and NCR are functionally distinct
General amino acid control
Nitrogen utilization and amino acid biosynthetic pathways are coordinately regulated
Integration of general and specific modes of regulation
Copyright © 2012 by the Genetics Society of America
Manuscript received March 20, 2011; accepted for publication August 1, 2011
1Corresponding authors: Wenner-Gren Institute, Stockholm University, Svante Arrhenius väg 20B, Stockholm SE-106 91, Sweden. E-mail: firstname.lastname@example.org; IBGC CNRS UMR5095,
1, rue Camille Saint Saëns, F-33077 Bordeaux Cedex, France. E-mail: email@example.com
Genetics, Vol. 190, 885–929 March 2012
SPS-sensor signaling: extracellular amino acid-induced nitrogen source uptake
Membrane transporter systems and compartmentalization
Regulation of pyrimidine metabolism
Regulation of the purine de novo synthesis pathway
Regulation of GTP synthesis
Regulation in response to growth phase
Identification of phosphate-responsive genes
Phosphorylation of Pho4 and subcellular localization in response to phosphate availability
Role of an intermediate metabolite (IP7) in the regulation of Pho81
Phosphate uptake and sensing
Purine phosphate connection: more signal molecules
Polyphosphates as a means to save and buffer intracellular phosphate
Regulation by noncoding RNAs
achievement of yeast research has been the determination of
the complete metabolic pathways for amino acid utilization as
carbon and nitrogen sources, amino acid biosynthesis, and the
conversion of amino acids to other metabolites including nu-
cleotides. Key reviews on these processes, of almost biblical
stature, by Cooper (1982a) and Jones and Fink (1982) are
notable since they summarized and integrated results from
both biochemical and genetic analyses and thereby provided
a solid framework to incorporate findings that have been
highlighted in subsequent major reviews (Hinnebusch 1992;
Johnston and Carlson 1992; Magasanik 1992). Extensive, al-
beit not fully complete, information regarding the metabolic
networks involving amino acids and nucleotides is available in
well-established databases with excellent user interfaces, e.g.,
the Saccharomyces Genome Database (SGD) (Hong et al.
2008) and the Kyoto Encyclopedia of Genes and Genomes
(KEGG) (Aoki-Kinoshita and Kanehisa 2007).
In cells, catabolic nitrogen source utilization and anabolic
amino acid and nucleotide biosynthetic pathways function
in parallel. These competing processes must be coordinated
to enable cells to manifest a proper response to nutrient
availability. A requisite for coordination of metabolism is the
ability to monitor concentrations of nutrients in the extra-
cellular environment and within cells (for review see Zaman
et al. 2008). Plasma membrane-localized sensors that re-
spond to the availability of diverse sets of nutrients, includ-
ing many nitrogen sources, have recently been identified.
N addition to being the building blocks of proteins, amino
acids have a central role in general metabolism. A major
These environmental sensors operate together with net-
works of intracellular sensing systems that are spread and
function in the cytosol, vacuole/endosome, mitochondria,
peroxisome, and nucleus. Furthermore, catabolic and ana-
bolic pathways generate multiple metabolic intermediates
that significantly contribute to the complexity of the chem-
ical composition of cells. These metabolic intermediates are
not necessarily inert, and there are examples of intermedi-
ates providing information (signals) regarding the metabolic
status of cells and exerting regulatory effects. Yeast cells can
clearly integrate multiple nutrient-based signals derived
from spatially separated sensing systems.
Here we focus on regulatory mechanisms and highlight
newly attained information regarding aspects of both catabolic
and anabolic processes affecting amino acid and nucleotide
metabolism. In addition, because nucleotide synthesis is phos-
phate consuming, regulation of phosphate uptake and utili-
zation is included. Specific examples have been chosen to
illustrate how multiple layers of metabolic control are co-
ordinated. Briefly, yeast cells possess suprapathway mecha-
nisms that, in response to metabolic changes, can reprogram
large-scale patterns of gene expression. Suprapathway control
is exerted at both the transcriptional and the translational
levels. In contrast to these general modes of control, cells can
also respond very precisely by regulating the activity of
specialized transcription factors that bind a particular metab-
olite and in response activate or repress the expression of
specific sets of genes. These mechanisms are complemented
by post-translational modes of regulation, which provide cells
P. O. Ljungdahl and B. Daignan-Fornier
with the means to rapidly adjust the catalytic properties of
enzymes, modulating the degradation rates of enzymes and
permeases and regulating the flow of metabolites in and out
of intracellular organelles.
Nitrogen source utilization: the flow of nitrogen to amino
acids, purines, and pyrimidines
Yeast cells react to the nitrogen content of the growth
environment by controlling nitrogen source uptake and by
regulating catabolic and anabolic processes. As reviewed by
Cooper (1982a) and schematically depicted in Figure 1,
yeast can use a variety of nitrogenous compounds as sole
sources of nitrogen for growth. Although some strain vari-
ability exists, all L-amino acids, with the exception of lysine,
histidine, and cysteine, can support growth as the sole ni-
trogen source (Table 1). However, each amino acid supports
a distinct rate of growth; in media with glucose as the main
carbon source, generation times vary from ?2 h (e.g., aspar-
agine, glutamine, and arginine) to .4 h (e.g., methionine
and tryptophan). The ability to use amino acids and other
nitrogenous compounds requires their internalization, and
accordingly, yeast cells possess multiple permeases to facil-
itate their transport across the plasma membrane (Table 4).
Notably, the presence of external amino acids induces the
expression of several broad-specificity permeases; hence,
amino acids induce their own uptake. This transcriptional
response is mediated by the plasma membrane localized
Ssy1-Ptr3-Ssy5 (SPS) sensor (reviewed in Ljungdahl 2009).
Once internalized, nitrogenous compounds can be used di-
rectly in biosynthetic processes, be deaminated to generate
ammonium, or serve as substrates of transaminases that
transfer amino groups to a-ketoglutarate to form glutamate
(reviewed in Cooper 1982a; Magasanik 1992; Magasanik
and Kaiser 2002). In cells grown on glucose, ammonium
can be assimilated by two anabolic reactions, i.e., the syn-
thesis of glutamate from ammonium and a-ketoglutarate
catalyzed by the NADPH-dependent glutamate dehydroge-
nase (GDH1) (reaction 1) (Figure 1), and the synthesis of
glutamine from ammonium and glutamate by glutamine
synthetase (GLN1) (reaction 2). In cells grown on ethanol
as a carbon source, a Gdh1 isozyme encoded by GDH3 is
expressed and contributes to the assimilation of ammonium
(Avendano et al. 1997; DeLuna et al. 2001). When gluta-
mine is the sole nitrogen source, the NADH-dependent glu-
tamate synthase (GLT1) is required to catalyze the synthesis
of glutamate (reaction 3). The catabolic release of ammonia
from glutamate (reaction 4) is catalyzed by the NAD+-linked
Figure 1 Schematic diagram of the
main pathways of nitrogen metabolism.
The entry routes of several nitrogen
sources into the central core reactions
are shown. The class A preferred and
class B nonpreferred nitrogen sources
are in green and red text, respectively.
The nitrogen of preferred nitrogen sour-
ces is incorporated into glutamate, and
shunted into pyruvate and a-ketogluta-
amino acids, aromatic amino acids, and
methionine (within box) is transferred to
a-ketoglutarate by transaminases form-
ing glutamate; the resulting deaminated
carbon skeletons are converted to non-
fusel oils (Hazelwood et al. 2008). Ni-
trogenous compounds are synthesized
with nitrogen derived from glutamate
or glutamine as indicated (blue arrows).
Central anabolic reactions 1 and 2 are
catalyzed by NADPH-dependent gluta-
mate dehydrogenase (GDH1) and gluta-
catabolic reactions 3 and 4 are catalyzed
by NADH-dependent glutamate syn-
thase (GLT1) and NAD+-linked gluta-
detailed descriptions of the pathways,
the reader is referred to the SGD (http://
Nitrogen and Phosphate Metabolism
glutamate dehydrogenase (GDH2). This latter reaction is
also required to provide ammonium for the synthesis of
glutamine when glutamate is the sole nitrogen source.
The central importance of glutamate and glutamine in
biosynthesis of nitrogenous compounds is illustrated in Fig-
ure 1 (blue arrows); ?85% of the total cellular nitrogen is
incorporated via the amino nitrogen of glutamate, and the
remaining 15% is derived from the amide nitrogen of glu-
tamine (Cooper 1982a).
Nitrogen source: quality of amino acids
The various nitrogen sources used by yeast are often
qualitatively referred to as being preferred (good) or non-
preferred (poor). This less-than-precise classification has
been empirically based on two criteria. The first criterion is
how well the individual compounds support growth when
present as sole source of nitrogen. The second criterion
reflects the finding that preferred nitrogen sources generally
repress processes required for the utilization of nonpreferred
nitrogen sources (reviewed in Cooper 1982a; Magasanik
1992; Magasanik and Kaiser 2002). Nitrogen regulation of
transcription is a general suprapathway response that is com-
monly referred to as nitrogen catabolite repression (NCR).
NCR primarily functions to ensure that cells selectively use
preferred nitrogen sources when they are available, and in
the absence of a preferred nitrogen source, the general de-
repression of NCR-regulated genes enables cells to indis-
criminately scavenge alternative, nonpreferred nitrogen
sources. The classification of nitrogen sources is not abso-
lute, and their repressive effects can vary significantly be-
tween different yeast strain backgrounds. For example,
ammonium and, to a lesser extent glutamate are repressing
nitrogen sources for S1278b-derived strains, whereas, for
many S288c-derived strains, they are not, even though these
nitrogen sources promote high rates of growth (Magasanik
and Kaiser 2002). Genetic analyses have shown that the
phenotypic differences between these genetic backgrounds
are multifactorial and not fully understood (Magasanik and
Kaiser 2002; Georis et al. 2009a).
Godard et al. (2007) carefully analyzed the patterns of
gene expression in prototrophic wild-type cells (S1278b)
growing in media containing glucose as the carbon source
and different sources of sole nitrogen, including 16 individ-
ual amino acids. Importantly, the patterns of gene expres-
sion were monitored in cells from logarithmically expanding
cultures fully adapted to growth with each individual
Table 1 Compilation of literature values: generation times and glutamate and glutamine pool sizes in cells grown on various sole
Generation time (hours.minutes)
mmol 100 mg21
Preferred class Aa: high-moderate active NCR/high-moderate active UPR/inactive GAAC
Intermediatea: slight active NCR/moderate active UPR/inactive GAAC
Intermediatea: inactive NCR/inactive-slight active UPR/inactive GAAC
Non-preferred class Ba: inactive NCR/slight active UPR/active GAAC
aGodard et al. (2007).
cNiederberger et al. (1981).
P. O. Ljungdahl and B. Daignan-Fornier
nitrogen source. This analysis revealed several significant
findings. First, the yeast cultures grew at variable rates char-
acteristic for the nitrogen source (Table 1); however, in the
comparisons with gene expression patterns, no significant
variations in the levels of general stress response genes were
detected. Consequently, cells clearly adapt to the quality of
the nitrogen source to achieve a balanced state of growth.
Second, the pattern of gene expression in urea-grown cells
could be used as the reference for comparisons; urea sup-
ports intermediate growth and, notably, the major transcrip-
tional regulatory systems, i.e., NCR, general amino acid
control (GAAC), and the unfolded protein response (UPR),
as well as the SPS-sensing system, are not active. Third, the
ability of cells to sense the presence of extracellular amino
acids via the SPS-sensing pathway and to prioritize their
uptake is relatively independent of nitrogen source. Fourth,
several of the nitrogen sources could unambiguously be
classified as follows: class A, preferred nitrogen sources—
nitrogen-sensitive gene expression is repressed (NCR is ac-
tive), the UPR is moderately active, and GAAC is inactive;
conversely, class B, nonpreferred nitrogen sources—nitrogen-
sensitive gene expression is derepressed (NCR inactive), UPR
is less active, and GAAC is highly active (Table 1). Finally, as
pointed out by Godard et al. (2007), the utilization of the
preferred amino acids as nitrogen sources yields carbon skel-
etons that are readily integrated in metabolism (Figure 1). Six
of the seven preferred amino acids are substrates of trans-
aminases or deaminases that yield pyruvate (alanine and
serine), tricarboxylic acid (TCA) cycle intermediates oxaloac-
etate (asparagine and aspartate) or a-ketoglutarate (gluta-
mate and glutamine). The nonpreferred class B amino acids
are subject to transamination resulting in carbon skeletons
that are converted via the Ehrlich pathway to noncataboliz-
able and growth-inhibitory fusel oils (Hazelwood et al. 2008).
Biosynthesis of amino acids
As schematically depicted in Figure 2, yeast cells provided
with an appropriate source of carbon and ammonium can
synthesize all L-amino acids used in protein synthesis (Jones
and Fink 1982). Ammonia is incorporated during the forma-
tion of glutamate from a-ketoglutarate (reaction 1) by
NADPH-dependent glutamate dehydrogenase (GDH1), and
glutamine from glutamate (reaction 2) by glutamine synthe-
tase (GLN1) (reviewed in Magasanik 2003). The families of
amino acids derived from a common molecule are readily
identifiable and include the glutamate family (glutamate,
glutamine, arginine, proline, and lysine); the aromatic fam-
ily (phenylalanine, tyrosine, and tryptophan); the serine
family (serine, glycine, cysteine, and methionine); the aspar-
tate family (aspartate, asparagine, threonine, and the sulfur-
containing amino acids cysteine and methionine); and the
pyruvate family (alanine and the branched amino acids va-
line, leucine, and isoleucine). The histidine and nucleotide
biosynthetic pathways are connected. The importance of
glutamate and glutamine, and consequently the central core
reactions in nitrogen metabolism, becomes apparent by
highlighting their involvement in transamination reactions
required in the synthesis of each amino acid (Cooper 1982a;
Magasanik 1992; Magasanik and Kaiser 2002).
Nitrogen-regulated gene expression
NCR was first recognized as a physiological response in the
early 1960s, and the literature regarding NCR is extensive;
however, the primary mechanism underlying how cells sense
the overall nitrogen status remains unknown (Cooper 2002;
Magasanik and Kaiser 2002). This represents a major hole in
understanding and a challenge for the future. The aim of the
following discussion of NCR is to provide the basis for un-
derstanding the rapidly evolving concepts of how nitrogen
source utilization pathways are regulated. The gene names
defined as standard in the SGD will be used.
Although the nitrogen-sensing mechanism(s) operating
upstream of NCR remain elusive, a rather comprehensive
understanding of the downstream events of NCR can be
outlined as follows. NCR-sensitive genes are controlled by
a core set of regulatory components, including Ure2 and the
four GATA transcription factors Gln3, Gat1, Dal80, and Gzf3.
Gln3 and Gat1 function as activators of gene expression that
are efficiently targeted to the nucleus under conditions that
derepress the expression of NCR-sensitive genes. In contrast,
Dal80 and Gzf3 act as repressors that constitutively localize
to the nucleus. All four transcription factors possess zinc-
finger DNA-binding motifs that bind core GATAAG consen-
sus sequences present in the promoters of NCR-sensitive
genes. The ability of the GATA factors to compete for cis-
acting GATAAG sequence elements is influenced by nitrogen
source availability and is even modulated by events within
the nucleus (Georis et al. 2009b, 2011).
The expression of NCR-sensitive genes is constitutively
depressed by mutations that inactivate Ure2 (Drillien and
Lacroute 1972), indicating that Ure2 participates in repres-
sing gene expression in cells grown in the presence of pre-
ferred nitrogen sources (Wiame et al. 1985; Courchesne and
Magasanik 1988; Coschigano and Magasanik 1991). The de-
repression of NCR genes in the absence of Ure2 is largely
dependent on Gln3; cells lacking GLN3 are unable to dere-
press NCR-sensitive gene expression (Mitchell and Magasanik
1984; Minehart and Magasanik 1991). Cells carrying muta-
tions that inactivate URE2 are able to utilize nonpreferred
nitrogen sources even in the presence of preferred ones,
a finding that has been exploited to optimize industrial
fermentations (Salmon and Barre 1998). The inactivation
of Ure2 results in constitutive nuclear localization of Gln3.
Microscopic analysis and subcellular fractionation studies
suggest that a significant portion of Gln3 is membrane asso-
ciated in cells grown in the presence of a preferred nitrogen
source, which may have important consequences for the reg-
ulation of the Ure2–Gln3 interaction (Cox et al. 2002; Puria
et al. 2008). Gat1 also targets the nucleus in cells grown in
nonpreferred nitrogen sources (Kulkarni et al. 2006). How-
ever, in contrast to Gln3, Gat1 is not specifically excluded
from the nucleus, and the loss of Ure2 does not greatly affect
Nitrogen and Phosphate Metabolism
Gat1 localization. Consequently, Gat1 localization appears
largely independent of Ure2; other factors thus must be
important in determining Gat1 function (Georis et al. 2008,
2009a,b). This notion is consistent with the finding that Gzf3
interacts directly with Gat1 in the nucleus, an interaction that
regulates Gat1 promoter binding (Georis et al. 2009b).
With the notable exception of GLN3, the genes for the
other three GATA factors (GAT1, GZF3, and DAL80) are
expressed under the control of promoters containing multi-
ple GATAAG sequences, and their expression is sensitive to
NCR (Cunningham and Cooper 1991; Coffman et al. 1996;
Rowen et al. 1997; Soussi-Boudekou et al. 1997). These
factors participate in regulating each other’s expression
(cross-regulation), exhibiting either positive or negative
regulation dependent on their corresponding roles. In cer-
tain instances, the factors regulate their own expression
(Figure 3) (Coffman et al. 1997; Rowen et al. 1997;
Soussi-Boudekou et al. 1997; Georis et al. 2009b).
In growing cells, URE2 and GLN3 expression are not
tightly regulated in response to nitrogen (Coschigano and
Magasanik 1991; Georis et al. 2009b). Consequently, the
Ure2–Gln3 interaction provides cells with a stably expressed
regulatory complex, or switch, that can be rapidly controlled
to directly activate gene expression. The Ure2–Gln3 switch
appears to function as the master controller, which, together
with the overlapping regulatory activities of the GATA fac-
tors, enables cells to adjust GATA factor levels in a manner
appropriate for prevailing nitrogen source availability
(Zaman et al. 2008). Activation of the switch in cells grown
in the presence of nonrepressing (nonpreferred) nitrogen
sources results in the suprapathway induction of ?90 genes
(Table 2). Although several models have been proposed for
the regulation of the Ure2–Gln3 switch, the current litera-
ture does not support a consensus view, and clearly, deci-
phering the mechanism(s) controlling the Ure2–Gln3 switch
remains the Holy Grail of the NCR field.
Target of rapamycin (TOR) signaling and NCR
are functionally distinct
It has also been proposed that TOR signaling directly re-
gulates NCR by controlling the Ure2-mediated cytoplasmic
retention of Gln3 (Beck and Hall 1999). Consistent with
Figure 2 General scheme for the biosynthesis of amino acids from glucose and ammonia. Ammonia is incorporated during the formation of glutamate
from a-ketoglutarate (reaction 1) by NADPH-dependent glutamate dehydrogenase (GDH1) and of glutamine from glutamate (reaction 2) by glutamine
synthetase (GLN1). The transamination reactions transferring nitrogen from glutamate (yellow) or glutamine (green) are shown. For detailed descriptions
of the pathways, the reader is referred to the SGD (http://pathway.yeastgenome.org/) or KEGG (http://www.genome.jp/kegg/pathway.html) databases.
P. O. Ljungdahl and B. Daignan-Fornier
this notion, cells treated with rapamycin, a specific inhibitor
of the TORC1 complex (Loewith et al. 2002), exhibit dere-
pressed expression of NCR-sensitive genes. Rapamycin
treatment reduces levels of Gln3 phosphorylation, which
correlates with its nuclear targeting. In apparent support
of this model, the TORC1-regulated phosphatase Tap42-
Sit4, negatively controlled by TORC1, has been shown to
influence the extent of Gln3 phosphorylation (Beck and Hall
1999; Cardenas et al. 1999; Hardwick et al. 1999; Bertram
et al. 2000; Carvalho et al. 2001).
Although very important insights regarding NCR have
been gained by examining rapamycin inhibition of TORC1
signaling, and without doubt TORC1 activity can influence
NCR, this major signaling hub appears to operate indepen-
dently, perhaps in parallel of the nitrogen sensor that “nat-
urally” regulates NCR. Consistent with this notion, there is
accumulating evidence that rapamycin exerts its effects in
a manner that does not faithfully mimic nitrogen starvation
(Cox et al. 2004; Crespo et al. 2004; Kulkarni et al. 2006;
Georis et al. 2008, 2009a; Puria and Cardenas 2008; Puria
et al. 2008; Tate et al. 2009, 2010). For example, in direct
opposition to rapamycin treatment, a functional myc-tagged
Gln3 construct becomes hyperphosphorylated during nitro-
gen and carbon starvation (Cox et al. 2004; Kulkarni et al.
2006), and the phosphorylation status of Gln3 does not
affect its ability to bind Ure2 (Bertram et al. 2000). Also,
Gln3 phosphorylation levels do not correlate with the pres-
ence of preferred or nonpreferred nitrogen sources, the in-
tracellular localization of Gln3, or the capacity to support
NCR-sensitive transcription (Cox et al. 2004; Tate et al.
2005; Kulkarni et al. 2006). Consequently, the mechanisms
controlling Gln3 localization remain to be clarified.
Since the inactivation of TORC1 induces signals that
impinge on the NCR-mediated transcriptional control path-
way, it is imperative to distinguish between direct and
indirect effects. There are several examples where this has
been problematic. For example, in ammonium-grown cells,
the mutational inactivation of NPR1 results in Gln3-depen-
dent derepression of NCR-sensitive genes (Crespo et al.
2004). The kinase activity of Npr1 is required for proper
post-transcriptional control of several ammonium-sensitive
permeases (Boeckstaens et al. 2007). On the basis of experi-
ments indicating that Npr1 is rapidly dephosphorylated
upon rapamycin treatment (Schmidt et al. 1998), the dere-
pression of nitrogen-regulated genes was interpreted to sup-
port the placement of TORC1 in a pathway negatively
controlling NCR (Crespo et al. 2004). However, further anal-
ysis has shown that the derepression of NCR-regulated
genes is linked to the known requirement of Npr1 in facili-
tating efficient ammonium uptake, i.e., the nitrogen source
used in the initial studies. Indeed, NCR is active in npr1
mutants when ammonium uptake is restored using buffered
media (see Wiame et al. 1985) or in heterologous expression
of a non-Npr1-regulated ammonium transporter from the
fungus Hebeloma cylindrosporum (Feller et al. 2006). Con-
sistently, the presence of preferred amino acids glutamine,
serine, or asparagine also represses NCR-sensitive genes in
cells lacking Npr1 function (Tate et al. 2006). Also, Crespo
et al. (2004) reported that inactivating mutations affecting
the function of the E3-ubiquitin ligase Rsp5, or its associated
proteins Bul1/Bul2, restores repression of NCR-regulated
genes in cells lacking NPR1. In accordance with the current
understanding of these components, and their role in gov-
erning the stability of plasma membrane permeases (for re-
view see Lauwers et al. 2010), loss of Rsp5-mediated
ubiquitylation prevents the degradation of nitrogen-sensi-
tive permeases. Consequently, suppression of the npr1mu-
tant phenotype is accounted for by the increased capacity of
the npr1 rsp5 double mutants to take up ammonium (Feller
et al. 2006). These data demonstrate that Npr1 and TORC1
have indirect roles in regulating NCR, presumably by con-
trolling the functional expression of ammonium permeases.
Figure 3 Model of GATA factor and NCR-controlled gene expression.
The promoters of GAT1, GZF3, and DAL80 contain multiple GATAAG
sequences, and their expression is sensitive to NCR. These factors regulate
each other’s expression (cross-regulation) and in certain instances exhibit
partial autogenous regulation. GAT1 and DAL80 expression is primarily
dependent on Gln3 and Dal80; the expression of these factors is the
highest in cells grown under nonrepressive conditions. Inactivation of
GZF3 results in the derepressed expression of several NCR-sensitive genes
including GAT1, indicating that, in contrast to Dal80, Gzf3 is expressed at
functionally significant levels and active in the presence of repressing
nitrogen sources. Consistent with this latter finding, GZF3 expression is
induced by Gat1 under conditions when Gln3 is apparently inactive
(Rowen et al. 1997). Gzf3 maintains low levels of GAT1 expression by
competing with Gat1 at GATAAG-binding sites; in essence, these two
factors participate in an autoregulatory loop. Green lines and arrows in-
dicate positive regulation; red lines and bars indicate negative regulation;
and dashed lines reflect relatively weaker regulation. The model is mod-
ified from Coffman et al. (1997) and Georis et al. (2009a).
Nitrogen and Phosphate Metabolism
General amino acid control
As noted by Jones and Fink (1982), many enzymes in
multiple amino acid biosynthetic pathways are induced
in response to starvation for any amino acid. This supra-,
cross-pathway regulation is termed general amino acid
control, or GAAC (reviewed in Hinnebusch and Natarajan
2002; Hinnebusch 2005). Amino acid starvation can be
rapidly induced by the addition of antimetabolites [e.g.,
3-amino-1,2,4-triazole, a competitive inhibitor of imida-
zoleglycerol-phosphate dehydratase (HIS3) that catalyzes
the sixth step of histidine biosynthesis, and metsulfuron
methyl, an inhibitor of acetohydroxyacid synthase (Ilv2)
that catalyzes the first step of branched-chain amino acid
biosynthesis] or by the removal of an amino acid required
for growth of auxotrophic strains. GAAC is required for
survival of cells grown on media prepared with amino
acid compositions that elicit starvation through feedback
inhibition of enzymes in shared pathways. For example,
when cells are grown in the presence of both tyrosine and
phenylalanine, mutants lacking GAAC cannot grow on
media lacking tryptophan (Niederberger et al. 1981). In
either of the starvation conditions just described, cells
activate the expression of a large set of genes (.500)
(Figure 4C), including representatives in every amino acid
biosynthetic pathway, with the exception of cysteine (Ta-
ble 3) (Natarajan et al. 2001; Hinnebusch and Natarajan
The transcriptional activator Gcn4, which binds to pro-
moters of genes possessing the consensus UASGCREsequence
motif GAGTCA, mediates GAAC. GCN4 expression is induced
in starved cells at the translational level by a reinitiation
mechanism involving four short upstream open reading
frames (uORFs) (Mueller and Hinnebusch 1986). The anal-
ysis of how the GAAC pathway controls GCN4 expression
has defined the central mechanisms governing the initiation
of protein synthesis in eukaryotes and has provided the basis
for understanding translational control of gene expression
(Hinnebusch 2005; Altmann and Linder 2010). The mech-
anistic details of GAAC regulation have advanced to a very
precise level of understanding (Sonenberg and Hinnebusch
2009), and a detailed discussion is out of the scope of this
review. However, in subsequent sections, the role of GAAC as
integrated into the overall metabolic adjustments in growing
and nonstarved cells will be discussed, as will its role in the
transcriptional regulation of genes associated with amino
An outline of the GAAC pathway and the global conse-
quence of the induced expression of Gcn4 in metabolic reg-
ulation is presented in Figure 4. Briefly, upon amino acid
starvation, multiple tRNAs become deacylated (Zaborske
et al. 2009, 2010). Gcn2 has an auto-inhibited kinase do-
main that is allosterically activated in starved cells through
binding of uncharged tRNAs to an adjacent histidyl-tRNA
synthetase-like domain (Wek et al. 1989; Dong et al.
2000). The activated Gcn2 kinase phosphorylates the a-sub-
unit of eIF2, leading to reduced levels of ternary complex
(TC; eIF2-GTP-Met-tRNAiMet). The diminished levels of TC
decrease the efficiency of scanning ribosomes to reinitiate
translation, increasing the proportion of ribosomes that
reinitiate translation at GCN4. In addition to translational
control, GCN4 transcription is induced under conditions that
derepress NCR (Godard et al. 2007), and starvation leads to
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Category Experimentally verifieda
Amino acid – nitrogen metabolism
ASP3c, BAT2, CAR1, DAL1, DAL2,
DAL3, DAL7, DCG1, DUR1,-2, GDH2,
GDH3, GLN1, PUT1, PUT2, UGA1
AGP1, CAN1, DAL4, DAL5, DUR3, GAP1,
MEP1, MEP2, MEP3, PUT4, UGA4
DAL80, GAT1, GZF3
ATG14, CPS1, LAP4, PEP4, PRB1
ARG4, CHA1, GDH1, GLT1, NIT1, SDL1
Plasma membrane nitrogen uptake
DIP5, OPT1, OPT2. , PTR2
GCN4, MIG2, UGA3
AVT1, AVT4, AVT7, MOH1, VBA1,
NPR2, PMP1, RTS3, YGK3
AAH1, GUD1, NRK1, URK1
ECM37, LEE1, RNY1, RPS0B, RSM10,
SLX9, UGX2, YDL237w, YDR090c,
YJR011c, YLR149c, YLR257w, YOR052c
Mitochondrial carrier proteins
Nucleotide salvage pathways
ECM38, VID30, YHI9, YGR125w
aForty-one known NCR-regulated genes as compiled by (Godard et al. (2007).
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Nitrogen and Phosphate Metabolism