Structures of the hydrolase domain of zebrafish 10-formyltetrahydrofolate dehydrogenase and its complexes reveal a complete set of key residues for hydrolysis and product inhibition

Lin, Chi‐Chang; Chuankhayan, Phimonphan; Chang, Wei-Ju; Kao, Tseng Ting; Guan, Hongbing; Fun, Hoong Kun; Nakagawa, Atsushi; Fu, Tzu Fun; Chen, Chun‐Jung

doi:10.1107/s1399004715002928

Cited by 7 publications

(11 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BLAST 27 search revealed that the amino acid sequence of the N-terminal domain of HypX has a homology to that of the hydrolase domain of N 10 -formyl-tetrahydrofolate (N 10 -formyl-THF) dehydrogenase (FDH) 28 . Protein structure comparison by the DALI server 29 revealed the structural homology between the N-terminal domain of HypX and the hydrolase domain of FDH 30,31 , methionyl-t-RNA formyltransferase (FMT) 32,33 , and UDP-glucuronic acid dehydrogenase (ArnA) 34–36 (Fig. 2b and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The crystallographic analyses reveal that HypX consists of the N- and C-terminal domains that are structurally homologous to the hydrolase domain of FDH and enoyl-CoA hydratase/isomerase (ECH/ECI), respectively. The hydrolase domain of FDH catalyzes formyl-group transfer from N 10 -formyl-THF to ACP, for which His106, Ser108, and Asp142 act as a catalytic triad 30,31 . At first in this reaction, Asp142 abstracts a proton from the SH group in 4-phosphopantetheine that is a prosthetic group in ACP.…”

Section: Discussionmentioning

confidence: 99%

“…The resulting thiolate attacks nucleophilically the carbon atom of formyl group in N 10 -formyl-THF to produce an oxy-anion intermediate. The orientation of Asp142 is fixed by a hydrogen bond with πN of His106 30,31 . Ser106 is responsible for the fixation of the orientation of His106 by a hydrogen bond with τN of His106 30,31 .…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Structural characterization of HypX responsible for CO biosynthesis in the maturation of NiFe-hydrogenase

et al. 2019

View full text Add to dashboard Cite

Several accessory proteins are required for the assembly of the metal centers in hydrogenases. In NiFe-hydrogenases, CO and CN− are coordinated to the Fe in the NiFe dinuclear cluster of the active center. Though these diatomic ligands are biosynthesized enzymatically, detail mechanisms of their biosynthesis remain unclear. Here, we report the structural characterization of HypX responsible for CO biosynthesis to assemble the active site of NiFe hydrogenase. CoA is constitutionally bound in HypX. Structural characterization of HypX suggests that the formyl-group transfer will take place from N10-formyl-THF to CoA to form formyl-CoA in the N-terminal domain of HypX, followed by decarbonylation of formyl-CoA to produce CO in the C-terminal domain though the direct experimental results are not available yet. The conformation of CoA accommodated in the continuous cavity connecting the N- and C-terminal domains will interconvert between the extended and the folded conformations for HypX catalysis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural characterization of HypX responsible for CO biosynthesis in the maturation of NiFe-hydrogenase

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The crystal structure of the ALDH1L1 formyltransferase domain (4TT8), solved in the complex with the substrate analog 10-formyl-5,8-dideazafolate (10-fDDF), shows that the folate molecule sits at the end of a long cleft between the N- and C-terminal lobes of this domain (22). The formyl leaving group of the coenzyme is adjacent to catalytic residues H106 (17) and D142 (29) on one side while exposed to nucleophilic attack on the other.…”

Section: Resultsmentioning

confidence: 99%

“…An NMR solution structure of the ALDH1L1 ACP domain has been solved (PDB 2CQ8), and several crystal structures of the dehydrogenase domain of the rat enzyme and the formyltransferase domain from several species have been reported (14,18–22). The structure of the full-length protein, however, is still not available.…”

Section: Introductionmentioning

confidence: 99%

Modeling of interactions between functional domains of ALDH1L1

Horita

Krupenko

2017

Chemico-Biological Interactions

View full text Add to dashboard Cite

ALDH1L1, a member of the aldehyde dehydrogenase superfamily of enzymes, catalyzes the conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO2. The enzyme is a tetramer of identical subunits, with each subunit consisting of three functional domains that originated from unrelated genes. The N- and C-terminal domains are catalytic, while the intermediate domain transfers the reaction intermediate from the N- to the C-terminal domain. The intermediate domain is an acyl carrier protein, possessing the covalently attached 4′-phosphopantetheine (4-PP) prosthetic group. This prosthetic group is known to function as a swinging arm transferring intermediates between enzymes in complex biosynthetic reactions. Here we have applied computer modeling using available structures of the three functional domains of ALDH1L1 to evaluate the extent of flexibility within the full-length protein. This approach allowed us to define positions of the 4-PP arm within the two catalytic domains and to predict N-terminal:intermediate and intermediate:C-terminal domain interfaces. Our models further suggested high degree of flexibility within the full-length enzyme.

show abstract

Formyltetrahydrofolate Decarbonylase Synthesizes the Active Site CO Ligand of O₂-Tolerant [NiFe] Hydrogenase

et al. 2019

View full text Add to dashboard Cite

[NiFe] hydrogenases catalyze the reversible oxidation of molecular hydrogen into two protons and two electrons. A key organometallic chemistry feature of the NiFe active site is that the iron atom is co-coordinated by two cyanides (CN–) and one carbon monoxide (CO) ligand. Biosynthesis of the NiFe(CN)2(CO) cofactor requires the activity of at least six maturation proteins, designated HypA–F. An additional maturase, HypX, is required for CO ligand synthesis under aerobic conditions, and preliminary in vivo data indicated that HypX releases CO using N 10-formyltetrahydrofolate (N 10-formyl-THF) as the substrate. HypX has a bipartite structure composed of an N-terminal module similar to N 10-formyl-THF transferases and a C-terminal module homologous to enoyl-CoA hydratases/isomerases. This composition suggested that CO production takes place in two consecutive reactions. Here, we present in vitro evidence that purified HypX first transfers the formyl group of N 10-formyl-THF to produce formyl-coenzyme A (formyl-CoA) as a central reaction intermediate. In a second step, formyl-CoA is decarbonylated, resulting in free CoA and carbon monoxide. Purified HypX proved to be metal-free, which makes it a unique catalyst among the group of CO-releasing enzymes.

show abstract

Structures of the hydrolase domain of zebrafish 10-formyltetrahydrofolate dehydrogenase and its complexes reveal a complete set of key residues for hydrolysis and product inhibition

Abstract: Structures of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase from zebrafish and its complexes are reported.

Cited by 7 publications

References 46 publications

Structural characterization of HypX responsible for CO biosynthesis in the maturation of NiFe-hydrogenase

Structural characterization of HypX responsible for CO biosynthesis in the maturation of NiFe-hydrogenase

Modeling of interactions between functional domains of ALDH1L1

Formyltetrahydrofolate Decarbonylase Synthesizes the Active Site CO Ligand of O₂-Tolerant [NiFe] Hydrogenase

Contact Info

Product

Resources

About

Structures of the hydrolase domain of zebrafish 10-formyltetrahydrofolate dehydrogenase and its complexes reveal a complete set of key residues for hydrolysis and product inhibition

Abstract: Structures of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase from zebrafish and its complexes are reported.

Cited by 7 publications

References 46 publications

Structural characterization of HypX responsible for CO biosynthesis in the maturation of NiFe-hydrogenase

Structural characterization of HypX responsible for CO biosynthesis in the maturation of NiFe-hydrogenase

Modeling of interactions between functional domains of ALDH1L1

Formyltetrahydrofolate Decarbonylase Synthesizes the Active Site CO Ligand of O2-Tolerant [NiFe] Hydrogenase

Contact Info

Product

Resources

About

Formyltetrahydrofolate Decarbonylase Synthesizes the Active Site CO Ligand of O₂-Tolerant [NiFe] Hydrogenase