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Structure of putative tumor suppressor ALDH1L1.

ABSTRACT: Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP⁺-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO₂. Cryo-EM structures of tetrameric rat ALDH1L1 revealed the architecture and functional domain interactions of this complex enzyme. Highly mobile N-terminal domains, which remove formyl from 10-formyltetrahydrofolate, undergo multiple transient inter-domain interactions. The C-terminal aldehyde dehydrogenase domains, which convert formyl to CO₂, form unusually large interfaces with the intermediate domains, homologs of acyl/peptidyl carrier proteins (A/PCPs), which transfer the formyl group between the catalytic domains. The 4'-phosphopantetheine arm of the intermediate domain is fully extended and reaches deep into the catalytic pocket of the C-terminal domain. Remarkably, the tetrameric state of ALDH1L1 is indispensable for catalysis because the intermediate domain transfers formyl between the catalytic domains of different protomers. These findings emphasize the versatility of A/PCPs in complex, highly dynamic enzymatic systems.

SUBMITTER: Tsybovsky Y

PROVIDER: S-EPMC8748788 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Structure of putative tumor suppressor ALDH1L1.

Tsybovsky Yaroslav Y Sereda Valentin V Golczak Marcin M Krupenko Natalia I NI Krupenko Sergey A SA

Communications biology 20220110 1

Putative tumor suppressor ALDH1L1, the product of natural fusion of three unrelated genes, regulates folate metabolism by catalyzing NADP<sup>+</sup>-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and CO<sub>2</sub>. Cryo-EM structures of tetrameric rat ALDH1L1 revealed the architecture and functional domain interactions of this complex enzyme. Highly mobile N-terminal domains, which remove formyl from 10-formyltetrahydrofolate, undergo multiple transient inter-domain inte ...[more]

PMID: 35013550

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Project description:Folate (vitamin B9) is a common name for a group of coenzymes that function as carriers of chemical moieties called one-carbon groups in numerous biochemical reactions. The combination of these folate-dependent reactions constitutes one-carbon metabolism, the name synonymous to folate metabolism. Folate coenzymes and associated metabolic pathways are vital for cellular homeostasis due to their key roles in nucleic acid biosynthesis, DNA repair, methylation processes, amino acid biogenesis, and energy balance. Folate is an essential nutrient because humans are unable to synthesize this coenzyme and must obtain it from the diet. Insufficient folate intake can ultimately increase risk of certain diseases, most notably neural tube defects. More than 20 enzymes are known to participate in folate metabolism. Single-nucleotide polymorphisms (SNPs) in genes encoding for folate enzymes are associated with altered metabolism, changes in DNA methylation and modified risk for the development of human pathologies including cardiovascular diseases, birth defects, and cancer. ALDH1L1, one of the folate-metabolizing enzymes, serves a regulatory function in folate metabolism restricting the flux of one-carbon groups through biosynthetic processes. Numerous studies have established that ALDH1L1 is often silenced or strongly down-regulated in cancers. The loss of ALDH1L1 protein positively correlates with the occurrence of malignant tumors and tumor aggressiveness, hence the enzyme is viewed as a candidate tumor suppressor. ALDH1L1 has much higher frequency of non-synonymous exonic SNPs than most other genes for folate enzymes. Common SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717, and rs4646750 in ALDH1L1 exons characterize more than 97% of Europeans while additional common variants are found in other ethnic populations. The effects of these SNPs on the enzyme is not clear but studies indicate that some coding and non-coding ALDH1L1 SNPs are associated with altered risk of certain cancer types and it is also likely that specific haplotypes define the metabolic response to dietary folate. This review discusses the role of ALDH1L1 in folate metabolism and etiology of diseases with the focus on non-synonymous coding ALDH1L1 SNPs and their effects on the enzyme structure/function, metabolic role and association with cancer.

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Structure of putative tumor suppressor ALDH1L1.

Publications

Structure of putative tumor suppressor ALDH1L1.

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