Keywords: dihydrolipoate; 2-oxo acid dehydrogenase complex; radical species; redox state; thioredoxin.. and NADH, where R defines pyruvate, 2-oxoglutarate orthe 2-oxo acids with branched
Trang 1M I N I R E V I E W
2-Oxo acid dehydrogenase complexes in redox regulation
Role of the lipoate residues and thioredoxin
Victoria I Bunik
A.N.Belozersky Institute of Physico-Chemical Biology, Moscow State University, Russia
A number of cellular systems cooperate in redox regulation,
providing metabolic responses according to changes in the
oxidation (or reduction)of the redox active components of
a cell Key systems of central metabolism, such as the 2-oxo
acid dehydrogenase complexes, are important participants
in redox regulation, because their function is controlled by
the NADH/NAD+ratio and the complex-bound
dihydro-lipoate/lipoate ratio Redox state of the complex-bound
lipoate is an indicator of the availability of the reaction
substrates (2-oxo acid, CoA and NAD+)and thiol-disulfide
status of the medium Accumulation of the dihydrolipoate
intermediate causes inactivation of the first enzyme of the
complexes With the mammalian pyruvate dehydrogenase,
the phosphorylation system is involved in the
lipoate-dependent regulation, whereas mammalian 2-oxoglutarate
dehydrogenase exhibits a higher sensitivity to direct
regula-tion by the complex-bound dihydrolipoate/lipoate and
external SH/S-S, including mitochondrial thioredoxin Thioredoxin efficiently protects the complexes from self-inactivation during catalysis at low NAD+ As a result, 2-oxoglutarate dehydrogenase complex may provide succi-nyl-CoA for phosphorylation of GDP and ADP under conditions of restricted NAD+ availability This may be essential upon accumulation of NADH and exhaustion of the pyridine nucleotide pool Concomitantly, thioredoxin stimulates the complex-bound dihydrolipoate-dependent production of reactive oxygen species It is suggested that this side-effect of the 2-oxo acid oxidation at low NAD+
in vivowould be overcome by cooperation of mitochondrial thioredoxin and the thioredoxin-dependent peroxidase, SP-22
Keywords: dihydrolipoate; 2-oxo acid dehydrogenase complex; radical species; redox state; thioredoxin
Introduction
Regulation of metabolism dependent on the cellular redox
state has attracted increasing attention [1–5] The redox
state is characterized by the degree of oxidation or reduction
of various redox-active species of a cell Among these
species, pyridine nucleotides and thiol/disulfide compounds
are of special significance, as they interconnect many
enzymes of the multifaceted metabolic network On the
one hand, the steady-state ratios of NAD(P)H/NAD(P)+
and SH/S-S mediate the redox regulation through direct
effects on proteins Activities of many enzymes depend on
the redox state of the pyridine nucleotide pools, while
proteins with essential SH/S-S groups can be regulated by
post-translational modification involving cellular thiols and
disulfides [1,5–7] On the other hand, the NAD(P)H/
NAD(P)+and SH/S-S ratios are intimately related to the
cellular level of ROS Reduced pyridine nucleotides and thiols participate both in ROS formation and degradation The former process is effected by different NAD(P)H oxidases [8] and upon thiol oxidation [9,10], while the glutathione- and thioredoxin-dependent peroxidase reac-tions use NADPH and thiols to scavenge hydrogen peroxide and limit formation of radical species [11] At low concentrations, ROS are essential participants of the cellular redox regulation [3,11,12] Their extremely high reactivity allows for the fast local modification of proteins This can provide transient oxidative modifications against the reducing potential of the medium, e.g formation of
a protein disulfide bond in the reducing cytoplasm [13] However, the high reactivity also leads to cell destruction if cellular capacity to scavenge ROS is compromised This happens under pathological conditions where NAD(P)H/ NAD(P)+and SH/S-S ratios are decreased [14–17] While experiments with intact cells enable us to assess the net effects of redox perturbations that reflect integrated metabolic responses, dissecting the mechanisms of these overall responses requires investigation of the separate components of the metabolic network Among cellular systems, the 2-oxo acid dehydrogenase multienzyme com-plexes occupy key positions for redox regulation In the overall process (see reactions 1–5 in scheme below)involving sequential action of 2-oxo acid dehydrogenase (E1), dihydrolipoamide acyltransferase (E2)and dihydrolipo-amide dehydrogenase (E3), they split a carbon-carbon bond of the 2-oxo acid preserving its energy in acyl-CoA
Correspondence to V Bunik, A.N.Belozersky Institute of
Physico-Chemical Biology, Moscow State University,
Moscow 119899, Russia.
Fax: + 7 095 939 31 81, Tel.: + 7 095 939 14 56,
E-mail: bunik@genebee.msu.su
Abbreviations: E1, 2-oxo acid dehydrogenase; E2, dihydrolipoamide
acyltransferase; E3, dihydrolipoamide dehydrogenase; EPR,
electron paramagnetic resonance; ROS, reactive oxygen species.
(Received 23 July 2002, revised 10 December 2002,
accepted 11 December 2002)
Trang 2and NADH, where R defines pyruvate, 2-oxoglutarate or
the 2-oxo acids with branched carbon chain:
Thus, the catalytic action of the 2-oxo acid
dehydro-genase complexes directly influences the NADH/NAD+
ratio and involves the important biological SH/S-S
com-pounds, lipoic acid and CoA, with one of them (lipoate)
being covalently bound to the complexes
Sensitivity of the 2-oxo acid dehydrogenase complexes to
NADH/NAD+has long been recognized as a mechanism
of feedback control [18,19] Being operative in vivo [20], it
increases fluxes through pyruvate dehydrogenase complex
under more oxidizing conditions [2] However, the
SH/S-S-dependent regulation of the complexes, in particular, by the
complex-bound lipoate/dihydrolipoate ratio, has received
little attention, although some experiments suggested the
interaction of the complex-bound dihydrolipoate with
external disulfides [21,22] At the same time, there are
numerous studies of the antioxidant properties of free
lipoate [23–25] Free dihydrolipoate efficiently reduces
transcription factors [26] and thioredoxin [27], which are
well-known components of the redox regulation [5,11,28]
Because cellular lipoate/dihydrolipoate is mostly localized
to the 2-oxo acid dehydrogenase complexes, the interplay
between the complexes and other participants of redox
signaling is of great interest
An essential feature of the complex-bound lipoate/
dihydrolipoate couple is that its redox state is linked to the
irreversible reaction of the 2-oxo acid oxidation Because
of this, the lipoate redox state in vivo is defined by the
steady-state concentrations of the overall reaction
sub-strates (2-oxo acid, CoA and NAD+)rather than
thermodynamic equilibrium with cellular thiols Another
essential feature of the lipoate residues within the 2-oxo
acid dehydrogenase complexes arises from the crowding
effect Confinement of the complex-bound lipoate within
the volume of the enzyme complexes may result in unusual
properties of the compound, when compared to the same
quantity of the lipoate molecules distributed in bulk
solution In particular, neighbouring sulfur greatly
increa-ses the stability of the thiyl radical in dithiols compared to
monothiols [29] Additional stabilization of the lipoate
thiyl radicals may be expected within the network of the
interacting complex-bound lipoate residues Thus, the
complexes provide an excellent opportunity to study in vitro
the consequences of cellular compartmentalization of biologically active SH/S-S
Taking into account multiple pharmacological effects of free lipoate [23–25], we suggested that the lipoate clustering within the 2-oxo acid dehydrogenase complexes may be significant not only for the typical enzymatic catalysis, but also for cellular redox regulation, including cellular protec-tion against oxidative damage Our idea that the complex-bound lipoate possesses a function beyond its role as
a catalytic intermediate in the oxidative decarboxylation is
in good agreement with certain data about the complexes, which have not previously been given an adequate explan-ation Even a limited number of organisms from which the 2-oxo acid dehydrogenase complexes have been isolated have revealed structural variations of these systems that go beyond those essential for catalytic performance The variations are linked to different lipoate content in the complexes, including different degrees of oligomerization, different stoichiometries of catalytic components (in parti-cular, lipoyl moieties)and different localization of the lipoate residues They may be incorporated not only in the established lipoate holder, E2, but also in other components [30,31] Depending on the source and presence of substrates, the mostly investigated classic complexes (i.e those containing lipoate residues in E2 only)are built around oligomeric cores of 3, 24 or 60 E2 subunits Different types
of E2 may bear up to three lipoate residues, which is genetically determined [30,32,33] Surprisingly, more than half of the lipoyl moieties of the E2 oligomer [34–36], or two
of the three lipoyl-bearing domains of E2 [37,38], may be removed without significant change in the overall activity
in vitro.Yet microorganisms possessing pyruvate dehydro-genase complex with a decreased number of lipoyl domains are at a physiological disadvantage They exhibit decreased growth rates and are eventually washed-out from the mixed population containing the mutant and wild type cells [38,39] The physiological behaviour, however, is main-tained even with a reduced number of lipoyl groups as long
as the reach of the lipoyl moieties is not decreased That is, the mutant strain possessing E2 bearing the three lipoyl domains with only the outermost one lipoylated (the two inner lipoyl domains in this case do not contain the lipoyl group)behaved identically to the wild type under the conditions employed [38] Because such a mutant complex catalyzes pyruvate oxidation even 25% less efficiently than the complexes which are unable to provide the normal growth rates (with E2 containing one or two fully lipoylated domains)[38], the physiological advantage of the E2 with the three lipoyl domains cannot be ascribed entirely to the catalytic role of these domains Rather, the advantage appears to depend on the ability of the lipoyl group to protrude from the inner core of the complex, indicative of the biological significance of the complex-bound lipoate interaction with the surrounding medium
This paper reviews experimental evidence for the involve-ment of the complex-bound lipoate in such paracatalytic reactions, i.e those where the complex-bound lipoate escapes the catalytic route (reactions 1–5) The reactions underlie the SH/S-S-dependent regulation of the 2-oxo acid dehydrogenase complexes on different levels The basic level corresponds to self-regulation of the complexes by the complex-bound lipoate/dihydrolipoate ratio Involvement
Trang 3of external components in the lipoate-dependent reactions
extends this regulation to a higher level For instance,
production of ROS by the complexes and interchange of the
complex-bound dihydrolipoate/lipoate with external thiols
and disulfides, including thioredoxin, may be important for
ROS-dependent signaling Thus, the redox state of the
complex-bound lipoate creates a sensitive link between
the 2-oxo acid dehydrogenase reaction and surrounding
medium
Self-regulation of the complexes
by the redox state of the lipoate residues
As follows from the scheme of the overall 2-oxo acid
dehydrogenase reaction (reactions 1–5), the steady-state
ratio of the complex-bound lipoate/dihydrolipoate is a
func-tion of (a)concentrafunc-tions of the reacfunc-tion substrates and
products, (b)kinetic properties of the component enzymes,
E1, E2 and E3, and (c)their stoichiometry and interactions
within the complex During catalysis in the physiological
direction, the complex-bound lipoate is reduced to
dihydro-lipoate by the 2-oxo acid and CoA (reactions 1–3)and the
dihydrolipoate is reoxidized by NAD+in a FAD-dependent
process (reactions 4,5) The lipoate may be also reduced in
the backward reactions (5 and 4), upon preincubation with
NADH In the mitochondrial 2-oxoglutarate dehydrogenase
complex, this induces strong cooperativity among the active
sites of its first component, 2-oxoglutarate dehydrogenase,
upon 2-oxoglutarate binding, and complicates the kinetic
dependence of the reaction rate on 2-oxoglutarate [40]
Isolated from the complex, the 2-oxoglutarate
dehydro-genase component did not show such changes in response
to NADH However, the changes were observed after the
enzyme reduction with dihydrolipoate Similar
concentra-tion of other cellular thiols, such as glutathione, cysteine or
CoA, were ineffective [40] Thus, the lipoate residues of the
complex mediate the regulation of its first component by the
last product of the overall reaction, NADH
Reduction of the lipoate residues of the complexes in
the forward direction, i.e by 2-oxo acid and CoA
(reactions 1–3), when the following reoxidation by
NAD+ (reaction 5)is restricted, is accompanied by an
irreversible inactivation of E1 [41] The inactivation is
observed both in the presence and absence of O2 When
the complex-bound lipoate was reduced under anaerobic
conditions, the complex-bound thyil radical and a radical
fragment of 2-oxo acid were detected in spin trapping
experiments with a-phenyl-N-tert-butylnitrone and
5,5¢-dimethyl-1-pyrroline-N-oxide, respectively [42] Thus, the
E1 inactivation occurs upon 1e– reduction of the thiyl
radical of the complex-bound dihydrolipoate by the E1
catalytic intermediate (E1*S):
The resulting substrate-derived radical fragment (SÆ)
likely causes the observed E1 inactivation due to a
site-directed modification Efficiency of reaction 6 is provided by
the protein–protein interactions evolved to enable the
catalytic 2e–reduction of the lipoate by E1*S (reaction 2)
In the absence of O2, the dihydrolipoate thiyl radical is transiently formed upon equilibration of the complex redox centers In the presence of O2, the E3-bound FAD catalyzes 1e–oxidation of the complex-bound dihydrolipo-ate by oxygen, resulting in superoxide anion radical production [42] The thiyl radical of the complex-bound dihydrolipoate is an intermediate of this side reaction (Fig 1) The superoxide production by the complexes is competitive with the NAD+reduction Under conditions where less NAD+ is available, more superoxide is produced, and this leads to a higher steady-state concen-tration of complex-bound thiyl radicals and a concomi-tantly greater extent of enzyme inactivation by the 2-oxo acid plus CoA Saturation by NAD+protects from the 1e–oxidation of the dihydrolipoate intermediate by oxygen and prevents inactivation [41] Resistance of the overall activity to the superoxide anion radical produced is documented by the fact that superoxide dismutase does not prevent the inactivation This is in good accord with the independence of the inactivation on the presence of oxygen
The dihydrolipoate-mediated inactivation of E1 at low NAD+concentrations is more pronounced in mammalian than bacterial complexes [43] In contrast, inhibition of E3
by over-reduction with NADH is less efficient in mamma-lian complexes [44] Thus, the E3 inhibition seems to be the main response of bacterial complexes to NADH accumu-lation The mammalian complexes develop the E1-directed mechanisms of NADH- and dihydrolipoate-dependent regulation It is the initial stage of the substrate transfor-mation which is then affected
The 2-oxoglutarate dehydrogenase complex is more sensitive to the 2-oxo acid, CoA-induced inactivation than the pyruvate dehydrogenase complex [43] This agrees with the difference in the regulation of the two complexes by
Fig 1 Production of superoxide anion radical by the 2-oxo acid dehy-drogenase complexes Oxidation of the complex-bound dihydrolipoate
by oxygen is catalyzed by the E3-bound FAD Superoxide anion radical is detected in the reaction medium by appearance of the EPR signal corresponding to its reaction with the spin trap a-phenyl-N-tert-butylnitrone Appearance of the EPR signal is blocked either by the modification of the complex-bound FAD or by addition of superoxide dismutase.
Trang 4phosphorylation/dephosphorylation The latter mechanism
controls the function of eukaryotic pyruvate
dehydro-genase, whereas 2-oxoglutarate dehydrogenase is not
phos-phorylated Remarkably, the efficiency of the pyruvate
dehydrogenase phosphorylation depends on the state of the
complex-bound dihydrolipoate Thus, the redox regulation
of the eukaryotic pyruvate dehydrogenase is mediated by
the phosphorylation/dephosphorylation system, which thus
becomes the main transducer of multiple metabolic signals
Regarding the mammalian 2-oxoglutarate dehydrogenase
complex, the 2-oxo acid, CoA-dependent inactivation
through the complex-bound dihydrolipoate intermediate
appears to be the biologically relevant mechanism of redox
regulation The concentrations of 2-oxoglutarate and CoA
determined in mitochondria [45] are saturating for the
complex, while NADH/NAD+ratio varies depending on
the metabolic state Moreover, NAD+ is a substrate of
many mitochondrial enzymes, with the competition between
them further reducing the effective NAD+concentration
available for 2-oxoglutarate oxidation Hence, estimation of
the substrate ratio existing in vivo shows that it is in the
range where the self-inactivation of the 2-oxoglutarate
dehydrogenase complex upon accumulation of the
dihydro-lipoate intermediate may occur
As a result, the complex-bound lipoate allows the starting
component of the complexes, E1, to respond to the state of
the mitochondrial NAD+ and NADH pool The E1
activity is regulated both upon accumulation of NADH
and decrease of NAD+ The E1 inactivation at low NAD+
concentration prevents the side production of
dihydrolipo-ate-dependent reactive oxygen species (Fig 1)at the expense
of the 2-oxo acid oxidation Because a decrease in
concentration of mitochondrial pyridine nucleotides induces
antioxidant defense mechanisms [15,16], inactivation of the
2-oxo acid dehydrogenases under these conditions may be a
part of the integrated response It also may explain the
reduction of the 2-oxoglutarate dehydrogenase complex
activity observed under different pathological states [46]
Thiol-disulfide exchange between
the complex-bound lipoate and external
thiols/disulfides
In studies of mitochondria, disulfides inhibited
mitochond-rial respiration at the level of the 2-oxoglutarate
dehydro-genase reaction [21,22] Investigation of the purified
2-oxoglutarate dehydrogenase complex confirmed the
inhi-bition of the overall reaction by the low molecular mass
disulfides [41] The data pointed to the exchange of redox
equivalents between the complexes and the medium,
involving the dihydrolipoate intermediate Such an
exchange also enabled thiols or disulfides to protect the
complexes from the inactivation at low levels of NAD+
[43,47] With free disulfides which are substrates for E3
(R-lipoate), the flow of reducing equivalents from 2-oxo
acids to the disulfides was catalyzed by E3 [48,49] Because
dihydrolipoate is an efficient reductant of thioredoxin [27]
which may further direct reducing equivalents to different
processes [28], the 2-oxo acid dehydrogenase reaction
coupled to free lipoate reduction in the presence of
thio-redoxin may be a source of reducing equivalents for not
only NADH-dependent, but also thioredoxin-dependent
pathways For instance, the reaction provides reduction of disulfides in proteins such as insulin and thioredoxin reductase [48,49] Recently, an antioxidant defense system
in mycobacteria was discovered where the 2-oxoglutarate dehydrogenase complex provides reducing equivalents to the peroxiredoxin alkyl hydroperoxide reductase through
a thioredoxin-like protein [50]
Discovery of a specific mitochondrial thioredoxin with unknown protein targets [51] stimulated our interest in the potential interplay between the 2-oxo acid dehydrogenase complexes and thioredoxin via the complex-bound lipoate Unraveling an in vivo function of a thioredoxin species is complicated by the high chemical reactivity of its dithiol/ disulfide group, as it allows thioredoxin to participate in
a number of redox processes in vitro Study of cross-reactivity of thioredoxins and potential target proteins from different species helps to solve this problem through revealing specific protein–protein interactions promoting chemical reactions In particular, mitochondrial thio-redoxin rather inefficiently regulates the enzymes which are known to depend on the thioredoxin action [52] In contrast, it efficiently protects the 2-oxo acid dehydro-genase complexes from the 2-oxo acid, CoA-dependent inactivation [47,52] Studies using four types of the 2-oxo acid dehydrogenase complexes and 11 thioredoxin species support the biological relevance of this protection [43,47] Mitochondrial complexes are much more sensitive to the thioredoxin regulation than their bacterial counterparts This is due to a greater sensitivity of the mitochondrial complexes to the 2-oxo acid, CoA-induced inactivation, as the thioredoxin effect is related to alleviation of this inactivation On the other hand, among 11 thioredoxin species with comparable activity in the nonspecific insulin reduction test, mitochondrial thioredoxin is by far the most effective in protecting the complexes While some of thioredoxins are inactive or even decrease the complex activity, mitochondrial thioredoxin is protective down to
10)7M concentrations Correlation of the thioredoxin effects and protein structures revealed the following structural determinants of the specific action of mito-chondrial thioredoxin on the complexes [47]: (a)active site disulfide/dithiol group and the residues modulating its properties, (b)the interaction between the a3/310 and a1 helices and the length of the a1 helix and (c)the three charged residues on the thioredoxin surface opposite to the active site, which significantly influence polarization of the molecule Experimentally observed effects of different thioredoxins on the complexes (increase or decrease in the complex activity, or none)correlate with the dipole direction, while the effective thioredoxin concentrations correlate with the dipole magnitude It is known that steering effects of the long-range interactions between the electrostatic dipoles increase the number of effective collisions, i.e collisions which may be stabilized by short-range interactions [53] The observed correlation between polarization of the thioredoxin molecule and efficiency of its protection of the 2-oxo acid dehydroge-nase complexes points to long-range interactions as the basis for the effect of thioredoxin on the activity of the complex This relationship suggests coevolution of the interacting proteins, which would not be possible if the interactions were not relevant in vivo
Trang 5Thioredoxin protection from the 2-oxo acid,
CoA-induced inactivation of the dehydrogenase complexes, and
the recently published data on the high stability of the
thioredoxin thyil radical, which allows thioredoxin to
prevent the pro-oxidant action of the radical [54], support
the proposed mechanism of the inactivation (reaction 6)
Catalysing the dismutation of the dihydrolipoate thyil
radicals (Fig 2), thioredoxin prevents their adverse action
upon E1 The main component of cellular thiol buffer,
glutathione, also protects the complexes in vitro [41]
However, unlike thioredoxin, low molecular mass thiols
do not specifically bind to the complexes and their thiyl
radicals are known to possess pro-oxidant action [10,55,56]
Hence, regarding the overall mitochondrial metabolism,
glutathione cannot be an efficient scavenger of the
complex-bound thiyl radicals of dihydrolipoate
Protected by thioredoxin, the 2-oxoglutarate
dehydro-genase complex can produce energy at low NAD+not only
in the form of NADH, but also in the form of a macroergic
compound, succinyl-CoA The latter supports the only
reaction of substrate phosphorylation in the Krebs cycle,
catalyzed by succinyl thiokinase This may be especially
important in cases where leakage of pyridine nucleotides or
accumulation of NADH occurs due to disturbances in the
respiratory chain However, switching off the self-regulation
of the complexes by the dihydrolipoate thiyl radical,
thioredoxin also stimulates the side reaction of the
super-oxide anion radical production by the complexes (Fig 1) In
this regard, it is worth noting that mitochondrial
thiore-doxin is a substrate of mitochondrial thiorethiore-doxin
peroxi-dase, SP-22 [57] Reduced by the complex-bound
dihydrolipoate and coupled to SP-22, thioredoxin would
be able to scavenge hydrogen peroxide, which is formed
after dismutation of the superoxide anion radical produced
by the complexes as shown below:
Thus, thioredoxin interaction with the 2-oxo acid dehy-drogenase complexes under conditions of an increased steady-state concentration of dihydrolipoate may provide
a dual positive effect: relief of the pro-oxidant action of dihydrolipoate on E1 and scavenging of ROS produced by E3 As a result, cooperation of the 2-oxo acid dehydro-genase complexes, thioredoxin and SP-22 (reaction 7) enables oxidation of 2-oxo acids under increased concen-tration of the dihydrolipoate intermediate without accumu-lation of ROS
The antioxidant action of mitochondrial thioredoxin upon the 2-oxoglutarate dehydrogenase may be involved in the thioredoxin antiapoptotic action when cells are treated with tert-butyl hydroperoxide [58] Selective targeting of the 2-oxoglutarate dehydrogenase complex under oxidative stress [59] and inactivation of the 2-oxoglutarate dehydro-genase by tert-butyl hydroperoxide [60] favour this inter-pretation
Concluding remarks
Participation of the 2-oxo acid dehydrogenase complexes
in redox regulation is summarized in Fig 3 The interac-tion of the complexes with the surrounding medium may
be realized through the lipoate-dependent paracatalytic reactions Such reactions allow the 2-oxo acid dehydro-genase complexes to transform a signal in the form of metabolite concentrations into chemical reactions such as ROS production, thioredoxin reduction and E1 modifi-cation This network of reactions provides not only self-regulation of the complexes (Fig 3, boxed region), but also their interaction with the surrounding medium, which may be used in different signaling pathways Our data on the interplay between the mitochondrial complexes and thioredoxin favors participation of the complexes in the redox-dependent signaling through the thioredoxin sys-tem Other forms of such participation are known For example, the E1 subunit of the pyruvate dehydrogenase
Fig 3 Participation of the 2-oxo acid dehydrogenase complexes in the redox regulation of metabolism The redox state of the surrounding medium is sensed by the complexes through the concentrations of 2-oxo acid, CoA, NAD(H)and oxygen This external signal is trans-formed into the ratio of the complex-bound lipoate/dihydrolipoate Dependent on the input, this redox couple may regulate the activity of the starting component E1 (a), produce output to surrounding medium
in the form of ROS (b)and reduce thioredoxin and disulfides (c) Thioredoxin interferes with the self-regulation of the complexes (a), concomitantly stimulating ROS production (b) The latter may be overcome in the presence of SP-22.
Fig 2 Thioredoxin catalysis of the dismutation of the thiyl radicals of
the complex-bound dihydrolipoate intermediate.
Trang 6complex from Azotobacter vinelandii was shown to bind to
the fpr promoter region DNA, which is activated upon
cellular response to oxidative stress [61] In
Escheri-chia coli, this promoter is activated by the
redox-depend-ent transcription factor SoxS In view of the redox-sensing
function of the lipoate/dihydrolipoate couple of the
complex (Fig 3)and the intimate link between this
couple and E1, the E1 dissociation from the complex to
bind DNA may represent another form of the
lipoate-dependent response under conditions of oxidative stress
Acknowledgements
This work was supported by grants from DFG (438 17-159-92),
Volkswagen (I/69766)and Alexander von Humboldt (IV RUS 1003594
STP)Foundations Critical reading of the manuscript by Prof J J.
Mieyal (Case Western Reserve University, Cleveland, USA)is greatly
acknowledged.
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