Impact of missense mutations in the ALDH7A1 gene on enzyme structure and catalytic function

Korasick, David A.; Tanner, John J.

doi:10.1016/j.biochi.2020.09.016

Cited by 5 publications

(3 citation statements)

References 30 publications

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“…P6C is the 6‐membered ring analog of P5C and the substrate for l ‐pipecolate oxidase in the pipecolate lysine catabolic pathway (Hallen et al, 2013). The nonenzymatic hydrolysis of P6C produces α‐aminoadipate semialdehyde, the substrate for the lysine catabolic enzyme ALDH7A1 (Korasick & Tanner, 2021), which appears in both the saccharopine and pipecolate pathways of lysine catabolism. The alternative activity of PYCR1 in the reduction of P6C to l ‐pipecolic would impact lysine metabolism and potentially contribute to the metabolic mechanisms of inherited metabolic disorders of lysine metabolism.…”

Section: Discussionmentioning

confidence: 99%

Screening a knowledge‐based library of low molecular weight compounds against the proline biosynthetic enzyme 1‐pyrroline‐5‐carboxylate 1 (PYCR1)

Meeks,

Bogner,

Tanner

2024

Protein Science

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AbstractΔ1‐pyrroline‐5‐carboxylate reductase isoform 1 (PYCR1) is the last enzyme of proline biosynthesis and catalyzes the NAD(P)H‐dependent reduction of Δ1‐pyrroline‐5‐carboxylate to L‐proline. High PYCR1 gene expression is observed in many cancers and linked to poor patient outcomes and tumor aggressiveness. The knockdown of the PYCR1 gene or the inhibition of PYCR1 enzyme has been shown to inhibit tumorigenesis in cancer cells and animal models of cancer, motivating inhibitor discovery. We screened a library of 71 low molecular weight compounds (average MW of 131 Da) against PYCR1 using an enzyme activity assay. Hit compounds were validated with X‐ray crystallography and kinetic assays to determine affinity parameters. The library was counter‐screened against human Δ1‐pyrroline‐5‐carboxylate reductase isoform 3 and proline dehydrogenase (PRODH) to assess specificity/promiscuity. Twelve PYCR1 and one PRODH inhibitor crystal structures were determined. Three compounds inhibit PYCR1 with competitive inhibition parameter of 100 μM or lower. Among these, (S)‐tetrahydro‐2H‐pyran‐2‐carboxylic acid (70 μM) has higher affinity than the current best tool compound N‐formyl‐l‐proline, is 30 times more specific for PYCR1 over human Δ1‐pyrroline‐5‐carboxylate reductase isoform 3, and negligibly inhibits PRODH. Structure‐affinity relationships suggest that hydrogen bonding of the heteroatom of this compound is important for binding to PYCR1. The structures of PYCR1 and PRODH complexed with 1‐hydroxyethane‐1‐sulfonate demonstrate that the sulfonate group is a suitable replacement for the carboxylate anchor. This result suggests that the exploration of carboxylic acid isosteres may be a promising strategy for discovering new classes of PYCR1 and PRODH inhibitors. The structure of PYCR1 complexed with l‐pipecolate and NADH supports the hypothesis that PYCR1 has an alternative function in lysine metabolism.

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Section: Discussionmentioning

confidence: 99%

Screening a knowledge‐based library of low molecular weight compounds against the proline biosynthetic enzyme 1‐pyrroline‐5‐carboxylate 1 (PYCR1)

Meeks,

Bogner,

Tanner

2024

Protein Science

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“…We focused on the ALDH family because of its impact on several human diseases such as Sjogren-Larsson syndrome [30], type II hyperprolinemia, and mental retardation [31,32]. For example, ALDH7A1 deficiency results in pyridoxine-responsive epilepsies [34], and our analysis identified 13 common missense variants in ALDH7A1, which may also impact patients' risk of developing a neurological disorder, warranting further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in ALDH4A1 cause type II hyperprolinemia and result in mental retardation and convulsion [31,32]. Mutations in ALDH5A1 cause 4-hydroxybutyric aciduria [33], and mutations in ALDH7A1 cause pyridoxine-responsive epilepsies [34].…”

Section: Introductionmentioning

confidence: 99%

Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)

et al. 2021

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Human aldehyde dehydrogenase (ALDH) is a multigene family with 19 functional members encoding a class of diverse but important enzymes for detoxification or biotransformation of different endogenous and exogenous aldehyde substrates. Genetic mutations in the ALDH genes can cause the accumulation of toxic aldehydes and abnormal carbonyl metabolism and serious human pathologies. However, the physiological functions and substrate specificity of many ALDH genes are still unknown. Although many genetic variants of the ALDH gene family exist in human populations, their phenotype or clinical consequences have not been determined. Using the most comprehensive global human Genome Aggregation Database, gnomAD, we annotated here 1350 common variants in the 19 ALDH genes. These 1350 common variants represent all known genetic polymorphisms with a variant allele frequency of ≥0.1% (or an expected occurrence of ≥1 carrier per 500 individuals) in any of the seven major ethnic groups recorded by gnomAD. We detailed 13 types of DNA sequence variants, their genomic positions, SNP ID numbers, and allele frequencies among the seven major ethnic groups worldwide for each of the 19 ALDH genes. For the 313 missense variants identified in the gnomAD, we used two software algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant From Tolerant (SIFT), to predict the consequences of the variants on the structure and function of the enzyme. Finally, gene constraint analysis was used to predict how well genetic mutations were tolerated by selection forces for each of the ALDH genes in humans. Based on the ratio of observed and expected variant numbers in gnomAD, the three ALDH1A gene members, ALDH1A1, ALDH1A2, and ALDH1A3, appeared to have the lowest tolerance for loss-of-function mutations as compared to the other ALDH genes (# observed/# expected ratio 0.15–0.26). These analyses suggest that the ALDH1A1, ALDH1A2, and ALDH1A3 enzymes may serve a more essential function as compared with the other ALDH enzymes; functional loss mutations are much less common in healthy human populations than expected. This informatic analysis may assist the research community in determining the physiological function of ALDH isozymes and associate common variants with clinical phenotypes.

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Biochemical, structural, and computational analyses of two new clinically identified missense mutations of ALDH7A1

Korasick,

Buckley,

Palpacelli

et al. 2024

Chemico-Biological Interactions

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Impact of missense mutations in the ALDH7A1 gene on enzyme structure and catalytic function

Cited by 5 publications

References 30 publications

Screening a knowledge‐based library of low molecular weight compounds against the proline biosynthetic enzyme 1‐pyrroline‐5‐carboxylate 1 (PYCR1)

Screening a knowledge‐based library of low molecular weight compounds against the proline biosynthetic enzyme 1‐pyrroline‐5‐carboxylate 1 (PYCR1)

Annotation of 1350 Common Genetic Variants of the 19 ALDH Multigene Family from Global Human Genome Aggregation Database (gnomAD)

Biochemical, structural, and computational analyses of two new clinically identified missense mutations of ALDH7A1

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