Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism

MADEN, B. Edward H.

doi:10.1042/0264-6021:3500609

Cited by 99 publications

(115 citation statements)

References 140 publications

(355 reference statements)

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“…Apart from this reaction, all other subsequent reduction steps of C 1 -bodies seem to be catalysed by unrelated enzymes in aceto-and methanogens as indicated in figure 1 by blue and violet arrows and enzymes for aceto-and methanogenesis, respectively. This finding makes even clearer the above-mentioned fact that the C 1 -bodies methenyl, methylene and methyl are carried by dissimilar molecules, methanopterins in methanogens and folates in acetogens [32].…”

Section: Introductionmentioning

confidence: 80%

Beating the acetyl coenzyme A-pathway to the origin of life

Nitschke

Russell

2013

Phil. Trans. R. Soc. B

116

174

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Attempts to draft plausible scenarios for the origin of life have in the past mainly built upon palaeogeochemical boundary conditions while, as detailed in a companion article in this issue, frequently neglecting to comply with fundamental thermodynamic laws. Even if demands from both palaeogeochemistry and thermodynamics are respected, then a plethora of strongly differing models are still conceivable. Although we have no guarantee that life at its origin necessarily resembled biology in extant organisms, we consider that the only empirical way to deduce how life may have emerged is by taking the stance of assuming continuity of biology from its inception to the present day. Building upon this conviction, we have assessed extant types of energy and carbon metabolism for their appropriateness to conditions probably pertaining in those settings of the Hadean planet that fulfil the thermodynamic requirements for life to come into being. Wood–Ljungdahl (WL) pathways leading to acetyl CoA formation are excellent candidates for such primordial metabolism. Based on a review of our present understanding of the biochemistry and biophysics of acetogenic, methanogenic and methanotrophic pathways and on a phylogenetic analysis of involved enzymes, we propose that a variant of modern methanotrophy is more likely than traditional WL systems to date back to the origin of life. The proposed model furthermore better fits basic thermodynamic demands and palaeogeochemical conditions suggested by recent results from extant alkaline hydrothermal seeps.

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Section: Introductionmentioning

confidence: 80%

Beating the acetyl coenzyme A-pathway to the origin of life

Nitschke

Russell

2013

Phil. Trans. R. Soc. B

116

174

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“…The methyl group of methylated substrates is transferred to THF, yielding methyl-THF (51), which has to be oxidized to CO 2 in order to generate the reducing equivalents for reduction of CO 2 to CO. However, the first step in oxidation, methyl-THF to methylene-THF, is highly endergonic (⌬G 0 = ϭ ϩ23 kJ/mol [52])-so endergonic that, in organisms such as E. coli or eukaryotes, the methyl group is trapped as methyl-THF and can be released only by demethylation and not by oxidation. But acetogens growing on methyl groups containing substrates somehow have to oxidize methyl-THF.…”

Section: Discussionmentioning

confidence: 99%

Heterotrimeric NADH-Oxidizing Methylenetetrahydrofolate Reductase from the Acetogenic Bacterium Acetobacterium woodii

Bertsch¹,

Öppinger²,

Hess³

et al. 2015

J. Bacteriol.

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The methylenetetrahydrofolate reductase (MTHFR) of acetogenic bacteria catalyzes the reduction of methylene-THF, which is highly exergonic with NADH as the reductant. Therefore, the enzyme was suggested to be involved in energy conservation by reducing ferredoxin via electron bifurcation, followed by Na ؉ translocation by the Rnf complex. The enzyme was purified from Acetobacterium woodii and shown to have an unprecedented subunit composition containing the three subunits RnfC2, MetF, and MetV. The stable complex contained 2 flavin mononucleotides (FMN), 23.5 ؎ 1.2 Fe and 24.5 ؎ 1.5 S, which fits well to the predicted six [4Fe4S] clusters in MetV and RnfC2. The enzyme catalyzed NADH:methylviologen and NADH:ferricyanide oxidoreductase activity but also methylene-tetrahydrofolate (THF) reduction with NADH as the reductant. The NADH:methylene-THF reductase activity was high (248 U/mg) and not stimulated by ferredoxin. Furthermore, reduction of ferredoxin, alone or in the presence of methylene-THF and NADH, was never observed. MetF or MetVF was not able to catalyze the methylene-THFdependent oxidation of NADH, but MetVF could reduce methylene-THF using methyl viologen as the electron donor. The purified MTHFR complex did not catalyze the reverse reaction, the endergonic oxidation of methyl-THF with NAD ؉ as the acceptor, and this reaction could not be driven by reduced ferredoxin. However, addition of protein fractions made the oxidation of methyl-THF to methylene-THF coupled to NAD ؉ reduction possible. Our data demonstrate that the MTHFR of A. woodii catalyzes methylene-THF reduction according to the following reaction: NADH ؉ methylene-THF ¡ methyl-THF ؉ NAD ؉ . The differences in the subunit compositions of MTHFRs of bacteria are discussed in the light of their different functions. IMPORTANCEEnergy conservation in the acetogenic bacterium Acetobacterium woodii involves ferredoxin reduction followed by a chemiosmotic mechanism involving Na ؉ -translocating ferredoxin oxidation and a Na ؉ -dependent F 1 F o ATP synthase. All redox enzymes of the pathway have been characterized except the methylenetetrahydrofolate reductase (MTHFR). Here we report the purification of the MTHFR of A. woodii, which has an unprecedented heterotrimeric structure. The enzyme reduces methylene-THF with NADH. Ferredoxin did not stimulate the reaction; neither was it oxidized or reduced with NADH. Since the last enzyme with a potential role in energy metabolism of A. woodii has now been characterized, we can propose a quantitative bioenergetic scheme for acetogenesis from H 2 plus CO 2 in the model acetogen A. woodii.A cetogenic bacteria are a group of strictly anaerobic bacteria that can grow lithoautotrophically by reduction of carbon dioxide with molecular hydrogen to acetate (1, 2). CO 2 is reduced in the Wood-Ljungdahl pathway, which is the only pathway known to combine CO 2 fixation with the synthesis of ATP (3-5). CO 2 reduction proceeds via formate, formyltetrahydrofolate (THF), and methenyl-, methylene-, and methyl-THF to ...

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“…The linear sequence of reductions has no feedback, and the C 1 groups at intermediate oxidation states do not increase in complexity. Instead, these reductions (leading to intermediate C 1 states that would be unstable in solution) are carried out on evolutionarily refined folate cofactors [93]. The topology of the WL pathway becomes self-amplifying only if the larger and more complex biosynthetic network for these cofactors is considered together with that of the C 1 substrate, requiring that a longer feedback loop be maintained than the mere substrate loop in the other fixation pathways.…”

Section: Network-autocatalysis In Carbon-fixation Pathwaysmentioning

confidence: 99%

The compositional and evolutionary logic of metabolism

2012

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Metabolism is built on a foundation of organic chemistry, and employs structures and interactions at many scales. Despite these sources of complexity, metabolism also displays striking and robust regularities in the forms of modularity and hierarchy, which may be described compactly in terms of relatively few principles of composition. These regularities render metabolic architecture comprehensible as a system, and also suggests the order in which layers of that system came into existence. In addition metabolism also serves as a foundational layer in other hierarchies, up to at least the levels of cellular integration including bioenergetics and molecular replication, and trophic ecology. The recapitulation of patterns first seen in metabolism, in these higher levels, motivates us to interpret metabolism as a source of causation or constraint on many forms of organization in the biosphere. Many of the forms of modularity and hierarchy exhibited by metabolism are readily interpreted as stages in the emergence of catalytic control by living systems over organic chemistry, sometimes recapitulating or incorporating geochemical mechanisms. We identify as modules, either subsets of chemicals and reactions, or subsets of functions, that are re-used in many contexts with a conserved internal structure. At the small molecule substrate level, module boundaries are often associated with the most complex reaction mechanisms, catalyzed by highly conserved enzymes. Cofactors form a biosynthetically and functionally distinctive control layer over the small-molecule substrate. The most complex members among the cofactors are often associated with the reactions at module boundaries in the substrate networks, while simpler cofactors participate in widely generalized reactions. The highly tuned chemical structures of cofactors (sometimes exploiting distinctive properties of the elements of the periodic table) thereby act as 'keys' that incorporate classes of organic reactions within biochemistry. Module boundaries provide the interfaces where change is concentrated, when we catalogue extant diversity of metabolic phenotypes. The same modules that organize the compositional diversity of metabolism are argued, with many explicit examples, to have governed long-term evolution. Early evolution of core metabolism, and especially of carbon-fixation, appears to have required very few innovations, and to have used few rules of composition of conserved modules, to produce adaptations to simple chemical or energetic differences of environment without diverse solutions and without historical contingency. We demonstrate these features of metabolism at each of several levels of hierarchy, beginning with the small-molecule metabolic substrate and network architecture, continuing with cofactors and key conserved reactions, and culminating in the aggregation of multiple diverse physical and biochemical processes in cells.Content from this work may be used under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 licence.

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Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism

Cited by 99 publications

References 140 publications

Beating the acetyl coenzyme A-pathway to the origin of life

Beating the acetyl coenzyme A-pathway to the origin of life

Heterotrimeric NADH-Oxidizing Methylenetetrahydrofolate Reductase from the Acetogenic Bacterium Acetobacterium woodii

The compositional and evolutionary logic of metabolism

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