Evolutionary origin and functional diversification of aminotransferases

Koper, Kaan; Han, Shunsheng; Casas-Pastor, Delia; Yoshikuni, Yasuo; Maéda, Hiroshi

doi:10.1016/j.jbc.2022.102122

Cited by 44 publications

(66 citation statements)

References 347 publications

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“…Reaction specificity is determined by the conformation of the active site as well as how residues interact with PLP and the substrates. For aminotransferases, these enzymes typically form functional homomultimers with interfacial PLP-containing active sites, where transamination reactions proceed via substrate binding, amino group transfer, and product release [41].…”

Section: Resultsmentioning

confidence: 99%

“…The overall structural organization and active site architecture of PSAT are conserved with other members of the class IV family of aminotransferases [41], and phosphoserine aminotransferases from eukaryotic and prokaryotic organisms [46]. Evolutionary conservation scores for PSAT (pdb 3e77; subunit A) from the ConSurf DataBase [38,39], which are derived from sequence alignments of amino acid homologs with known structure, illustrate that more conserved (negative ConSurf score) regions localize near the active sites ( Figure 4.B ).…”

Section: Resultsmentioning

confidence: 99%

“…To provide a better understanding of the impact of missense substitutions on protein function, we examined the results of our assay in the context of mechanistic, structural, and evolutionary features of the human phosphoserine aminotransferase isoform 1 (PSAT) protein. PSAT belongs to the large family of fold type I pyridoxal phosphate (PLP; active form of vitamin b6) cofactordependent enzymes, and more specifically, the class IV group of aminotransferases [40,41] In PLP-dependent enzymes the cofactor serves two ubiquitous functions in catalysis: to form a reactive Schiff base covalent linkage with the substrate amino group and to act as an electron sink to stabilize intermediate states [42][43][44]. Reaction specificity is determined by the conformation of the active site as well as how residues interact with PLP and the substrates.…”

Section: Mapping Functional Effects To Protein Structure and Conserva...mentioning

confidence: 99%

“…All rights reserved. No reuse allowed without permission.The copyright holder for this preprint this version posted January 15, 2023. ; https://doi.org/10.1101/2023.01.11.523651 doi: bioRxiv preprint aminotransferases, these enzymes typically form functional homomultimers with interfacia PLP-containing active sites, where transamination reactions proceed via substrate binding, amino group transfer, and product release[41]. PHP) to phosphoserine[45].…”

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confidence: 99%

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Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps

Xie

Sirr

et al. 2023

Preprint

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Loss of function mutations in PHGDH, PSAT1, and PSPH cause a set of rare, autosomal recessive diseases known as Neu-Laxova syndrome (NLS) or serine-deficiency disorders. The diseases present with a broad range of phenotypes, including lethality, severe neurological manifestations, seizures, and intellectual disability. However, because L-serine supplementation, especially if started early in pregnancy, can ameliorate and in some cases even prevent symptoms, knowledge of pathogenic variants is highly actionable. Recently, our laboratory established a yeast-based assay for human PSAT1 function. We have now applied it at scale to assay the functional impact of 1,914 SNV-accessible amino acid substitutions. Our results agree well with clinical interpretations and protein structure-function relationships, supporting the use of our data as functional evidence under the ACMG interpretation guidelines. In addition to assaying the functional impact of individual variants in yeast haploid cells, we can assay pairwise combinations of PSAT1 alleles that recapitulate human genotypes, including compound heterozygotes, in yeast diploids. Results from this diploid assay successfully distinguish patient genotypes from those of healthy carriers and agree well with disease severity. Finally, we present a linear model that can accurately predict biallelic function in diploids using information from the individual allele measurements in haploids. Taken together, our work provides an example of how large-scale functional assays in model systems can be powerfully applied to the study of a rare disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Mapping Functional Effects To Protein Structure and Conserva...mentioning

confidence: 99%

mentioning

confidence: 99%

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Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps

Xie

Sirr

et al. 2023

Preprint

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“…However, in pdx3 mutants, PMP increases due to the lack of PMP oxidase activity and there is a deficit in PLP, and thus the PMP:PLP ratio is not maintained (see scheme in Figure 8). During transaminase reactions that allow the interconversion of amino and keto acids (Koper et al, 2022), PMP is a natural intermediate derived from the coenzyme PLP, that facilitates the transfer of an amino group to a keto acid to make an amino acid (Figure 8). An increase in PMP levels (as seen in pdx3 ) may drive the equilibrium in favor of amino acid formation (which we refer to as the “N-gear”, Figure 8).…”

Section: Discussionmentioning

confidence: 99%

PDX3 is important for carbon/nitrogen balance in Arabidopsis associated with distinct environmental conditions

Steensma

Eisenhut

Colinas

et al. 2022

Preprint

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To survive and proliferate in diverse environments with varying climate and nutrient availability, plants modulate their metabolism. Achieving a balance between carbon (C) and nitrogen (N) use such that growth and defense mechanisms can be appropriately controlled is critical for plant fitness. The identification of factors that regulate C/N utilization in plants can make a significant contribution to optimization of plant health. Here we show that pyridox(am)ine 5'-phosphate oxidase (PDX3), which regulates vitamin B6 homeostasis, influences C/N balance. The B6 vitamer imbalance resulting from loss of PDX3 leads to over-accumulation of nitrogenous compounds. A combination of increased glutamate dehydrogenase activity, impairment in the photorespiratory cycle and inappropriate use of endogenous ammonium fuel the metabolic imbalance. Growth at elevated CO2 levels further exacerbates the pdx3 phenotypes. Interestingly, serine supplementation rescues growth under high CO2 likely bypassing the phosphorylated pathway of biosynthesis suggesting that this amino acid is an important commodity. We show that PDX3 function appears dispensable upon thermomorphogenesis, a condition that favors C metabolism. Furthermore, while a low ammonium to nitrate ratio likely accounts for overstimulation of salicylic acid (SA) defense responses in pdx3 lines that compromises growth, a basal level of SA protects against loss of PDX3 biochemical function. Overall, the study highlights environmental scenarios where vitamin B6 homeostasis, as managed by the salvage pathway enzyme PDX3, is critical and provides insight into how plants reprogram their metabolism under such conditions.

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Synthesis of 3‐Phenylserine by a Two‐enzyme Cascade System with PLP Cofactor

Xu,

Tan,

et al. 2024

Chemistry A European J

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A two‐enzyme cascade system containing ω‐transaminase (ω‐TA) and L‐threonine aldolase (L‐ThA) was reported for the synthesis of 3‐Phenylserine starting from benzylamine, and PLP was utilized as the only cofactor in these both two enzymes reaction system. Based on the transamination results, benzylamine was optimized as an advantageous amino donor as confirmed by MD simulation results. This cascade reaction system could not only facilitate the in situ removal of the co‐product benzaldehyde, enhancing the economic viability of the reaction, but also establish a novel pathway for synthesizing high‐value phenyl‐serine derivatives. In our study, nearly 95% of benzylamine was converted, yielding over 54% of 3‐Phenylserine under the optimized conditions cascade reaction.

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Evolutionary origin and functional diversification of aminotransferases

Cited by 44 publications

References 347 publications

Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps

Predicting the functional effect of compound heterozygous genotypes from large scale variant effect maps

PDX3 is important for carbon/nitrogen balance in Arabidopsis associated with distinct environmental conditions

Synthesis of 3‐Phenylserine by a Two‐enzyme Cascade System with PLP Cofactor

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