Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme <scp>ALDH4A1</scp> by <scp>trans‐4‐hydroxy‐L‐proline</scp>

Bogner, Alexandra N; Stiers, Kyle M.; McKay, Cole; Becker, Donald F.; Tanner, John J.

doi:10.1002/pro.4131

Cited by 4 publications

(2 citation statements)

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“…Multiple sequence alignment reveals that the residues related to catalytic reactions in the ALDH‐SF are highly conserved, including the catalytic residues Cys296, the proton transfer residues Arg172, Glu262 and Glu471, the cofactor coordination residues Lys186 and Glu394, and two auxiliary residues Asn163 and Gly293 (Figure 1D ). [ 24 , 25 , 26 ]…”

Section: Resultsmentioning

confidence: 99%

“…Multiple sequence alignment reveals that the residues related to catalytic reactions in the ALDH-SF are highly conserved, including the catalytic residues Cys296, the proton transfer residues Arg172, Glu262 and Glu471, the cofactor coordination residues Lys186 and Glu394, and two auxiliary residues Asn163 and Gly293 (Figure 1D). [24][25][26] SNDH with a C-terminal His-tag was expressed in Escherichia coli and purified. SDS-PAGE analysis results showed that the molecular weight of SNDH is consistent with the theoretical size (54.4 kDa).…”

Section: Sndh Is a Member Of The Aldh Familymentioning

confidence: 99%

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Structural Insight into the Catalytic Mechanisms of an L‐Sorbosone Dehydrogenase

Li,

Deng,

Hou

et al. 2023

Advanced Science

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L‐Sorbosone dehydrogenase (SNDH) is a key enzyme involved in the biosynthesis of 2‐keto‐L‐gulonic acid , which is a direct precursor for the industrial scale production of vitamin C. Elucidating the structure and the catalytic mechanism is essential for improving SNDH performance. By solving the crystal structures of SNDH from Gluconobacter oxydans WSH‐004, a reversible disulfide bond between Cys295 and the catalytic Cys296 residues is discovered. It allowed SNDH to switch between oxidation and reduction states, resulting in opening or closing the substrate pocket. Moreover, the Cys296 is found to affect the NADP+ binding pose with SNDH. Combining the in vitro biochemical and site‐directed mutagenesis studies, the redox‐based dynamic regulation and the catalytic mechanisms of SNDH are proposed. Moreover, the mutants with enhanced activity are obtained by extending substrate channels. This study not only elucidates the physiological control mechanism of the dehydrogenase, but also provides a theoretical basis for engineering similar enzymes.

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Section: Resultsmentioning

confidence: 99%

Section: Sndh Is a Member Of The Aldh Familymentioning

confidence: 99%

Structural Insight into the Catalytic Mechanisms of an L‐Sorbosone Dehydrogenase

Li,

Deng,

Hou

et al. 2023

Advanced Science

View full text Add to dashboard Cite

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Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans‐4‐hydroxy‐L‐proline

et al. 2021

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Aldehyde dehydrogenase 4A1 (ALDH4A1) catalyzes the final steps of both proline and hydroxyproline catabolism. It is a dual substrate enzyme that catalyzes the NAD + -dependent oxidations of L-glutamate-γ-semialdehyde to L-glutamate (proline metabolism), and 4-hydroxy-L-glutamate-γ-semialdehyde to 4-erythro-hydroxy-L-glutamate (hydroxyproline metabolism). Here we investigated the inhibition of mouse ALDH4A1 by the six stereoisomers of proline and 4-hydroxyproline using steady-state kinetics and X-ray crystallography. Trans-4-hydroxy-L-proline is the strongest of the inhibitors studied, characterized by a competitive inhibition constant of 0.7 mM, followed by L-proline (1.9 mM). The other compounds are very weak inhibitors (approximately 10 mM or greater). Insight into the selectivity for L-stereoisomers was obtained by solving crystal structures of ALDH4A1 complexed with trans-4-hydroxy-L-proline and trans-4-hydroxy-D-proline. The structures suggest that the 10-fold greater preference for the L-stereoisomer is due to a serine residue that hydrogen bonds to the amine group of trans-4-hydroxy-L-proline. In contrast, the amine group of the D-stereoisomer lacks a direct interaction with the enzyme due to a different orientation of the pyrrolidine ring. These results suggest that hydroxyproline catabolism is subject to substrate inhibition by trans-4-hydroxy-L-proline, analogous to the known inhibition of proline catabolism by L-proline. Also, drugs targeting the first enzyme of hydroxyproline catabolism, by elevating the level of trans-4-hydroxy-L-proline, may inadvertently impair proline catabolism by the inhibition of ALDH4A1.

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Amino acid metabolism genes associated with immunotherapy responses and clinical prognosis of colorectal cancer

Peng

Zheng

Guo

et al. 2022

Front. Mol. Biosci.

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Based on amino acid metabolism-related genes (AAMRGs), this study aimed at screening out key prognosis-related genes and finding the underlying correlation between the amino acid metabolism and tumor immune microenvironment of colorectal cancer. A total of 448 amino acid metabolism-related genes were obtained from MsigDB. The risk signature was built based on differential expression genes, univariate Cox, and LASSO analyses with 403 patients’ data downloaded from the TCGA database. Survival analysis and independence tests were performed to confirm the validity of the risk signature. Single-sample gene set enrichment analysis (ssGSEA), tumor mutation burden (TMB), the score of tumor immune dysfunction and exclusion (TIDE), the immunophenoscore obtained from The Cancer Immunome Atlas database, and the IC50 of drugs were used to find the relationship among the risk signature, immune status, immunotherapy response, and drug sensitivity of colorectal cancer. We identified five amino acid metabolism-related genes for the construction of the risk signature, including ENOPH1, ACAT1, ALDH4A1, FAS, and ASPG. The low-risk group was significantly associated with a better prognosis (p < 0.0001). In the entire set, the area under the curve (AUC) for 1, 3, and 5 years was 0.717, 0.734, and 0.764, respectively. We also discovered that the low-risk subgroup was related to more activity of immune cells, had higher expression of some immune checkpoints, and was more likely to benefit from immunotherapy. ssGSEA revealed that except the processes of glutamine histidine, lysine, tyrosine, and L-phenylalanine metabolism, the other amino acid metabolism pathways were more active in the samples with the low risk scores, whereas the activities of synthesis and transportation of most amino acids were similar. Hedgehog signaling, WNT/β-catenin signaling, mitotic, notch signaling, and TGF-β signaling were the top five pathways positively associated with the risk score. To sum up, AAMRGs were associated with the immune microenvironment of CRC patients and could be applied as biomarkers to predict the prognosis and immunotherapy response of patients.

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Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans‐4‐hydroxy‐L‐proline

Cited by 4 publications

References 44 publications

Structural Insight into the Catalytic Mechanisms of an L‐Sorbosone Dehydrogenase

Structural Insight into the Catalytic Mechanisms of an L‐Sorbosone Dehydrogenase

Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans‐4‐hydroxy‐L‐proline

Amino acid metabolism genes associated with immunotherapy responses and clinical prognosis of colorectal cancer

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