The crystal structure of a class II fructose-1,6-bisphosphate aldolase shows a novel binuclear metal-binding active site embedded in a familiar fold

Cooper, Samuel J.; Leonard, Gordon A.; McSweeney, Seán; Thompson, Andrew; Naismith, James H.; Qamar, Seema; Plater, A.; Berry, Alan; Hunter, William N.

doi:10.1016/s0969-2126(96)00138-4

Cited by 114 publications

(119 citation statements)

References 47 publications

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“…A nonenzymatic glycolysis is accelerated by transition metals (5), and Zn(II) ions are involved in the catalytic mechanism of class I aldolases (21,22). Therefore, we screened for the effects of different metal ions.…”

Section: Resultsmentioning

confidence: 99%

Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice

Messner

Driscoll

Piedrafita

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The evolutionary origins of metabolism, in particular the emergence of the sugar phosphates that constitute glycolysis, the pentose phosphate pathway, and the RNA and DNA backbone, are largely unknown. In cells, a major source of glucose and the large sugar phosphates is gluconeogenesis. This ancient anabolic pathway (re-)builds carbon bonds as cleaved in glycolysis in an aldol condensation of the unstable catabolites glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, forming the much more stable fructose 1,6-bisphosphate. We here report the discovery of a nonenzymatic counterpart to this reaction. The in-ice nonenzymatic aldol addition leads to the continuous accumulation of fructose 1,6-bisphosphate in a permanently frozen solution as followed over months. Moreover, the in-ice reaction is accelerated by simple amino acids, in particular glycine and lysine. Revealing that gluconeogenesis may be of nonenzymatic origin, our results shed light on how glucose anabolism could have emerged in early life forms. Furthermore, the amino acid acceleration of a key cellular anabolic reaction may indicate a link between prebiotic chemistry and the nature of the first metabolic enzymes.T he metabolic network is a large cellular system that generates life's building blocks including amino acids, nucleotides, and lipids. Most of the metabolic pathways that participate in this network are well understood, but their evolutionary origin remains an unsolved problem. The network contains many reactive and unstable intermediates, yet its topological organization is widely conserved and considered ancient. It has therefore been extensively debated to what extent this structure could be the result of Darwinian selection and thus be of postgenetic origin or whether the metabolic network topology dates back to a nonenzymatic chemistry (1-4). A series of recently discovered chemical networks provide evidence for the latter. In the presence of simple inorganic ions as found in Archean sediment, and under conditions that are reminiscent of the chemistry that operates in cells, nonenzymatic reactions replicate essential topological elements of the most central metabolic pathways. Nonenzymatic chemical reactions currently replicate glycolysis (including the EmbdenMeyerhof-Parnas pathway, the Entner-Doudoroff pathway, and their many variants), the pentose phosphate pathway, the catabolic reactions of the TCA cycle, and the formation of the methyl group donor S-adenosylmethionine (5-8). Moreover, reactions of glycolysis and the pentose phosphate pathway, as well as reactions replicating the oxidative TCA cycle, can each occur in distinct but unifying reaction milieus, respectively. This implies that simple inorganic catalysts were shaping the topological structure of the metabolic network. In other words, the reactions that sugar phosphates undergo in the presence of the highest concentrated transition metal in Archean sediment [Fe(II)] and the reactions that TCA intermediates undergo in the presence of sulfate radicals are reflected i...

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Section: Resultsmentioning

confidence: 99%

Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice

Messner

Driscoll

Piedrafita

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…5). Each subunit (denoted A and B) folds into an (␣/␤) 8 barrel as seen in structures of other bacterial class II aldolases (15,16,20,37).…”

Section: Resultsmentioning

confidence: 99%

“…TBP is specifically targeted for cleavage by the E. coli D-tagatose-1,6-bisphosphate aldolase (ecTBPA), another class II aldolase. The crystal structures of ecFBPA (15,16) and ecTBPA (20) are similar, yet the mechanism for substrate (i.e. stereoisomer) discrimination is not apparent from a comparison of the respective active sites.…”

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confidence: 99%

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Characterization, Kinetics, and Crystal Structures of Fructose-1,6-bisphosphate Aldolase from the Human Parasite, Giardia lamblia

Galkin

Kulakova

Melamud

et al. 2007

Journal of Biological Chemistry

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Class I and class II fructose-1,6-bisphosphate aldolases (FBPA), glycolytic pathway enzymes, exhibit no amino acid sequence homology and utilize two different catalytic mechanisms. The mammalian class I FBPA employs a Schiff base mechanism, whereas the human parasitic protozoan Giardia lamblia class II FBPA is a zinc-dependent enzyme. In this study, we have explored the potential exploitation of the Giardia FBPA as a drug target. Giardia lamblia, a flagellated protozoan, is the most common disease-causing parasite in developed countries. G. lamblia is also responsible for the most frequently diagnosed infective disease in developing countries (for a recent review see Ref.

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“…The three latter enzymes display an (␣͞␤) 8 fold, whereas fuculose-1-phosphate aldolase does not. On this basis, it has been suggested that the class II aldolases fall into two distinct categories (37). On the basis of sequence identity and metal-binding preferences, class II aldolases exhibiting an (␣͞␤) 8 fold can be further subdivided into (i) fructose-1,6-bisphosphate and tagatose-1,6-bisphosphate aldolases, which share 23% sequence identity and bind Zn 2ϩ , and (ii) 2-dehydro-3-deoxygalactarate aldolase, unrelated in sequence to either of the above enzymes and preferentially binding Mg 2ϩ .…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of a bifunctional aldolase–dehydrogenase: Sequestering a reactive and volatile intermediate

Manjasetty

Powlowski

Vrielink

2003

Proc. Natl. Acad. Sci. U.S.A.

137

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The crystal structure of the bifunctional enzyme 4-hydroxy-2-ketovalerate aldolase (DmpG)͞acylating acetaldehyde dehydrogenase (DmpF), which is involved in the bacterial degradation of toxic aromatic compounds, has been determined by multiwavelength anomalous dispersion (MAD) techniques and refined to 1.7-Å resolution. Structures of the two polypeptides represent a previously unrecognized subclass of metal-dependent aldolases, and of a CoA-dependent dehydrogenase. The structure reveals a mixed state of NAD ؉ binding to the DmpF protomer. Domain movements associated with cofactor binding in the DmpF protomer may be correlated with channeling and activity at the DmpG protomer. In the presence of NAD ؉ a 29-Å-long sequestered tunnel links the two active sites. Two barriers are visible along the tunnel and suggest control points for the movement of the reactive and volatile acetaldehyde intermediate between the two active sites. E nzymatic channeling is a process by which intermediates are moved directly between active sites in a sequential reaction pathway without equilibrating with the bulk phase (1, 2). Channeling processes are particularly advantageous over the free diffusion of reaction products through the bulk solvent because they can protect chemically labile intermediates from breakdown, prevent loss of nonpolar intermediates by diffusion across cell membranes, or protect the cell from toxic intermediates. Crystallographic studies on a number of different enzyme systems involved in substrate channeling (3-11) have revealed important structural factors that mediate intersubunit or interdomain communication and facilitate the efficient transfer of intermediates between distant active sites.A bifunctional aldolase-dehydrogenase catalyzes the final two steps of the meta-cleavage pathway for catechol, an intermediate in many bacterial species in the degradation of phenols, toluates, naphthalene, biphenyls and other aromatic compounds (reviewed in ref. 12). Thus, 4-hydroxy-2-ketovalerate aldolase (DmpG; EC 4.1.3.-) and acetaldehyde dehydrogenase (acylating) (DmpF; EC 1.2.1.10) from a methylphenol-degrading pseudomonad convert 4-hydroxy-2-ketovalerate to pyruvate and acetyl-CoA by way of the intermediate acetaldehyde (Scheme 1).The two enzymes are tightly associated with each other (13,14). Whereas the aldolase appears to be inactive when expressed without the dehydrogenase, the dehydrogenase retains some activity when expressed in the absence of aldolase (14), suggesting that at least the dehydrogenase active site is distinct from that of the aldolase. Several lines of evidence are consistent with channeling of acetaldehyde between the active sites. For example, the conversion of 4-hydroxy-2-ketovalerate to acetyl-CoA occurs Ϸ20 times faster than that of acetaldehyde to acetyl-CoA, and the K m for acetaldehyde exceeds 50 mM, a physiologically irrelevant concentration (J.P., unpublished data). In addition, it has been shown that the aldolase activity is stimulated by the addition of the dehydrogenase cofactor to t...

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The crystal structure of a class II fructose-1,6-bisphosphate aldolase shows a novel binuclear metal-binding active site embedded in a familiar fold

Cited by 114 publications

References 47 publications

Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice

Nonenzymatic gluconeogenesis-like formation of fructose 1,6-bisphosphate in ice

Characterization, Kinetics, and Crystal Structures of Fructose-1,6-bisphosphate Aldolase from the Human Parasite, Giardia lamblia

Crystal structure of a bifunctional aldolase–dehydrogenase: Sequestering a reactive and volatile intermediate

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