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Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 283
Eric J. Mallack ◽  
Kerry Gao ◽  
Marc Engelen ◽  
Stephan Kemp

The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype–phenotype correlation in ALD. Since 1999, most ABCD1 (likely) pathogenic and benign variants have been reported in the ABCD1 Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in ABCD1. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1–2 (transmembrane domain spanning region) and 6–9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.

2022 ◽  
Bing Zhang ◽  
Zihe Rao ◽  
Haitao Yang ◽  
Shan Sun ◽  
Yan Gao ◽  

The ATP-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the typical fold of canonical ABC exporters. Here, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, and an ATP analogue (AMP-PNP) at resolutions from 2.9 to 3.5 Å. In the ATP-bound state, the two nucleotide-binding domains (NBDs) form a "head-to-tail" dimer, but IrtAB has an unexpectedly occluded conformation, with the inner core forming a large hydrophilic cavity of about 4600 Å3. Comparison of the structure of the transporter in inward-facing and occluded conformations reveals that the NBD and the intracellular helical region of transmembrane domain (TMD) have an asymmetric allosteric mechanism when ATP binding/hydrolysis such that the one exhibits rigid-body rotation and the other moves in a concerted response as a rigid body. This study provides a molecular basis for the ATP-driven conformational changes that occur in IrtAB and an explanation as to how iron-loaded siderophores are imported into Mtb by IrtAB.

eFood ◽  
2021 ◽  
Hui Teng ◽  
Hongting Deng ◽  
Yuanju He ◽  
Qiyan Lv ◽  
Lei Chen

Flavonoids are widely existing compounds with enormous pharmacological effects from food and medicine. However, the low bioavailability in intestinal absorption and metabolism limits their clinical application. Intestinal efflux ABC (ATP binding cassette) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), act as "pumping doors" to regulate the efflux of flavonoids from intestinal epithelial cells into the intestinal cavity or the systemic circulation. The present review describes the critical effect of ABC transporters involved in the efflux of flavonoids which depend on its efflux direction. And the role of flavonoids for modulation of intestinal ABC transporters was emphasized and several examples were given. We summarized that the resistance effect of flavonoid-mediated multidrug on ABC transporters may influence the bioavailability of drugs, bioactive ingredients and/or toxic compounds upon dietary uptake. Meanwhile, flavonoids functionalized as reversing agents of the ABC transporter may be an important mechanism for unexpected food-drug, food-toxin or food-food interactions. The overview also indicates that elucidation of the action and mechanism of the intestinal metabolic enzymes-efflux transporters coupling will lay a foundation for improving the bioavailability of flavonoids <i>in vivo</i> and increasing their clinical efficacy.

2021 ◽  
Vol 23 (1) ◽  
pp. 116
Olamide Jeje ◽  
Reabetswe Maake ◽  
Ruan van Deventer ◽  
Veruschka Esau ◽  
Emmanuel Amarachi Iwuchukwu ◽  

The continuous threat of drug-resistant Klebsiella pneumoniae justifies identifying novel targets and developing effective antibacterial agents. A potential target is nicotinate nucleotide adenylyltransferase (NNAT), an indispensable enzyme in the biosynthesis of the cell-dependent metabolite, NAD+. NNAT catalyses the adenylation of nicotinamide/nicotinate mononucleotide (NMN/NaMN), using ATP to form nicotinamide/nicotinate adenine dinucleotide (NAD+/NaAD). In addition, it employs divalent cations for co-substrate binding and catalysis and has a preference for different divalent cations. Here, the biophysical structure of NNAT from K. pneumoniae (KpNNAT) and the impact of divalent cations on its activity, conformational stability and substrate-binding are described using experimental and computational approaches. The experimental study was executed using an enzyme-coupled assay, far-UV circular dichroism, extrinsic fluorescence spectroscopy, and thermal shift assays, alongside homology modelling, molecular docking, and molecular dynamic simulation. The structure of KpNNAT revealed a predominately α-helical secondary structure content and a binding site that is partially hydrophobic. Its substrates ATP and NMN share the same binding pocket with similar affinity and exhibit an energetically favourable binding. KpNNAT showed maximum activity and minimal conformational changes with Mg2+ as a cofactor compared to Zn2+, Cu2+ and Ni2+. Overall, ATP binding affects KpNNAT dynamics, and the dynamics of ATP binding depend on the presence and type of divalent cation. The data obtained from this study would serve as a basis for further evaluation towards designing structure-based inhibitors with therapeutic potential.

Michael Dean ◽  
Karobi Moitra ◽  
Rando Allikmets

The ATP-binding cassette (ABC) transporter superfamily comprises membrane proteins that efflux various substrates across extra- and intra-cellular membranes. Mutations in ABC genes cause 21 human disorders or phenotypes with Mendelian inheritance, including cystic fibrosis, adrenoleukodystrophy, retinal degeneration, cholesterol, and bile transport defects. Common polymorphisms and rare variants in ABC genes are associated with several complex phenotypes such as gout, gallstones, and cholesterol levels. Overexpression or amplification of specific drug efflux genes contributes to chemotherapy multidrug resistance. Conservation of the ATP-binding domains of ABC transporters defines the superfamily members, and phylogenetic analysis groups the 48 human ABC transporters into seven distinct subfamilies. While the conservation of ABC genes across most vertebrate species is high, there is also considerable gene duplication, deletion, and evolutionary diversification.

2021 ◽  
Vol 22 (24) ◽  
pp. 13565
Kristin Oepen ◽  
Hüseyin Özbek ◽  
Anja Schüffler ◽  
Johannes C. Liermann ◽  
Eckhard Thines ◽  

ATP-binding cassette (ABC) transporters are conserved in all kingdoms of life, where they transport substrates against a concentration gradient across membranes. Some ABC transporters are known to cause multidrug resistances in humans and are able to transport chemotherapeutics across cellular membranes. Similarly, BmrA, the ABC transporter of Bacillus subtilis, is involved in excretion of certain antibiotics out of bacterial cells. Screening of extract libraries isolated from fungi revealed that the C14 fatty acid myristic acid has an inhibitory effect on the BmrA ATPase as well as the transport activity. Thus, a natural membrane constituent inhibits the BmrA activity, a finding with physiological consequences as to the activity and regulation of ABC transporter activities in biological membranes.

2021 ◽  
Vol 12 ◽  
Fangmei Tang ◽  
Linbo Guan ◽  
Xinghui Liu ◽  
Ping Fan ◽  
Mi Zhou ◽  

BackgroundATP-binding cassette transporter A1 (ABCA1) has important roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport, and is implicated in lipid-related disorders. Genetic variants are involved in the pathogenesis of gestational diabetes mellitus (GDM). The objective of this study was to investigate the association of rs2230806 (R219K), a single nucleotide polymorphism (SNP) in the lipid-related gene, with the risk of GDM and related traits.MethodsThe SNP, rs2230806, was genotyped, and clinical and metabolic parameters were determined in 660 GDM patients and 1,097 control subjects. Genetic associations with related traits were also analyzed.ResultsThe genotype distributions were similar in GDM patients and normal controls. However, significant differences in the variables examined in the study subjects were noted across the three genotypes. The genotype at the rs2230806 polymorphism was significantly associated with HDL-cholesterol (HDL-C) levels and atherogenic index (AI) values in GDM patients and total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels in control subjects. Subgroup analysis showed that the polymorphism was associated with diastolic blood pressure, in addition to HDL-C levels and AI, in overweight/obese GDM patients, while it was associated with TC levels, AI, pre-pregnancy body mass index (BMI), and BMI at delivery in non-obese GDM patients. In addition, this polymorphism was associated with TC, LDL-C, and apoB levels in overweight/obese control subjects.ConclusionsThe rs2230806 polymorphism in the ABCA1 gene was associated with variations in atherometabolic traits in GDM patients, with characteristics of BMI dependency, but not with GDM. Our findings highlight a link between related phenotypes in women with GDM and genetic factors.

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