Modeling of interactions between functional domains of ALDH1L1

Abstract

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.

The Role of Single-Nucleotide Polymorphisms in the Function of Candidate Tumor Suppressor ALDH1L1

“…The two catalytic domains communicate via the intermediate domain, which is a structural and functional homolog of acyl carrier proteins (Donato et al, 2007; Strickland et al, 2010). Its prosthetic group, 4′-phosphopantetheine (4′-PP), functions as a flexible arm reaching into the catalytic centers on the N- and C-terminal domains (Horita and Krupenko, 2017) and transporting the reaction intermediate (formyl) from one center to the other ( Figure 3 ). The three domains of ALDH1L1 work in concert to enable the conversion of 10-formyl-THF to THF and NADPH production linked to the oxidation of formyl group to CO 2 .…”

Abnormal downregulation of 10‐formyltetrahydrofolate dehydrogenase promotes the progression of oral squamous cell carcinoma by activating PI3K/Akt/Rb pathway

“…Among humans, the ALDH1L1 gene has 23 exons that span about 77 kb on the long arm of chromosome 3 (3q21.2). The subsequent protein is a tetramer composed of 902 aa identical subunits 8 . In addition, ALDH1L1 regulates cell de novo purine biosynthesis, 9 degradation of formate 10 as well as methylation status 11 .…”

“…The subsequent protein is a tetramer composed of 902 aa identical subunits. 8 In addition, ALDH1L1 regulates cell de novo purine biosynthesis, 9 degradation of formate 10 as well as methylation status. 11 These pathways are essential for cell proliferation as well as abnormal folate metabolism, and are associated with cancer.…”

Probing Protein 4′-Phosphopantetheinylation in Single Living Cells

“…As one of the folate enzymes, it converts 10-formyltetrahydrofolate (10-FTHF) to tetrahydrofolate (THF) and CO 2 in an NADP + -dependent reaction via the assisting of 4PPTylation . Without 4PPTylation, the catalysis function of ALDH1L1 is impossible. , The folate-mediated one-carbon metabolism significantly influences cellular proliferation. , ALDH1L1 is downregulated in proliferating tumors, while its high expression leads to the inhibition of proliferation and ultimately results in apoptosis. − However, owing to the lack of facile and sensitive single-cell tools for the analysis of protein 4PPTylation, further in-depth exploration of the roles and related mechanism of the 4PPTylation of ALDH1L1 and other proteins in cells still remains elusive.…”