Interaction of α-Lipoic Acid with the Human Na+/Multivitamin Transporter (hSMVT)

Zehnpfennig, Britta; Wiriyasermkul, Pattama; Carlson, David A.; Quick, Matthias

doi:10.1074/jbc.m114.622555

Cited by 24 publications

(21 citation statements)

References 54 publications

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“…This observation is in stark contrast to the binding isotherm of MhsT-WT (Figure 5A), which was well fit to a rectangular hyperbola reaching a molar Trp:MhsT binding ratio of 2. 18 Rectangular hyperbolic isotherms have been described for LeuT-fold proteins where both substrate binding sites exhibit similar affinities, whereas more complex (i.e., biphasic) binding isotherms have been observed when the affinities in both sites differ by a factor of about 10 14, 21–23 (Figure 5B, C), suggesting that in the Y37C and F366C mutants, the S2 site has a lower affinity than that in the WT. Such disrupted S2 binding results in substantially reduced 3 H-Trp transport as reflected in lowered initial rates and V max values of 3 H-Trp transport as well (Figure 6).…”

Section: Resultsmentioning

confidence: 96%

Exploring Substrate Binding in the Extracellular Vestibule of MhsT by Atomistic Simulations and Markov Models

Abramyan

Quick

Xue

et al. 2018

J. Chem. Inf. Model.

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Neurotransmitter:sodium symporters (NSS) terminate neurotransmission through Na+-driven reuptake of cognate neurotransmitters. Crystallographically, whereas both substrates and inhibitors have been found to bind in the central binding (S1) site of NSS, inhibitors were found to bind to a second binding (S2) site in the extracellular vestibule (EV) of transporters for leucine (LeuT) and serotonin. Based on computational and experimental studies, we proposed that substrates bind to the S2 site of LeuT as well, and that substrate binding to the S2 site is essential for Na+-coupled symport. Recent binding experiments show that substrate (L-Trp) binding in the S2 site of MhsT, another bacterial NSS, is also central to the allosteric transport mechanism. Here, we used extensive molecular dynamics simulations combined with Markov state model analysis to investigate the interaction of L-Trp with the EV of MhsT, and identified potential binding poses of L-Trp as well as induced conformational changes in the EV. Our computational findings were validated by experimental mutagenesis studies, and shed light on the ligand binding characteristics of the EV of NSS, which may facilitate development of allosteric ligands targeting NSS.

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Section: Resultsmentioning

confidence: 96%

Exploring Substrate Binding in the Extracellular Vestibule of MhsT by Atomistic Simulations and Markov Models

Abramyan

Quick

Xue

et al. 2018

J. Chem. Inf. Model.

Self Cite

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“…The hSMVT system transports three important nutrients: the water-soluble vitamins biotin and pantothenic acid, and the metabolically important substrate, lipoate (Prasad et al 1997; Uchida et al 2015; Zehnfenning et al 2015). These nutrients are involved in multiple essential metabolic functions, including intermediary metabolism, protein synthesis, bone density and brain and immune function (Bonjour 1980; Uchida et al .…”

Section: Discussionmentioning

confidence: 99%

“…2015) and the metabolically important lipoate (Prasad et al . 1997; Zehnfenning et al . 2015), each with their own deficiency states and metabolic effects.…”

Section: Introductionmentioning

confidence: 99%

Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child

et al. 2016

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The human sodium-dependent multivitamin transporter (hSMVT) is a product of the SLC5A6 gene and mediates biotin, pantothenic acid and lipoate uptake in a variety of cellular systems. We report here the identification of mutations R94X, a premature termination, and R123L, a dysfunctional amino acid change, both in exon 3 of the SLC5A6 gene in a child using whole genome-scanning. At 15 months of age, the child showed failure to thrive, microcephaly and brain changes on MRI, cerebral palsy and developmental delay, variable immunodeficiency, severe gastro-esophageal reflux requiring a gastrostomy tube/fundoplication, osteoporosis and pathologic bone fractures. After identification of the SLC5A6 mutations, he responded clinically to supplemental administration of excess biotin, pantothenic acid and lipoate with improvement in clinical findings. Functionality of the two mutants was examined by 3H-biotin uptake assay following expression of the mutants in human-derived intestinal HuTu-80 and brain U87 cells. The results showed severe impairment in biotin uptake in cells expressing the mutants compared to those expressing wild-type hSMVT. Live cell confocal imaging of cells expressing the mutants showed the R94X mutant to be poorly tolerated and localized in the cytoplasm, while the R123L mutant was predominantly retained in the endoplasmic reticulum. This is the first reporting of mutations in the SLC5A6 gene in man, and suggests that this gene is important for brain development and a wide variety of clinical functions.

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“…2 Variants leading to an impaired SMVT protein function might result in an intracellular deficiency of its organic substrates, as it is the only known combined biotin, pantothenic acid, and lipoate uptake transporter. 1,14 Considering their metabolic functions, intracellular deficiencies of biotin, pantothenic acid, and lipoate can cause a wide variety of signs and symptoms. The recent report of an infant with variants in the SLC5A6 gene with severe clinical findings supports this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Genetic defect of the sodium‐dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency

et al. 2019

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The sodium‐dependent multivitamin transporter that facilitates the uptake of the water‐soluble vitamins biotin, pantothenic acid, and the vitamin‐like substance lipoate is coded by the SLC5A6 gene. Variants in this gene cause a relatively novel treatable metabolic disorder. Here we describe the second case. A 17‐month‐old girl presented with hypoglycemia (2.0 mmol/L) and severe metabolic acidosis (pH 6.87), leading to resuscitation. Her history revealed feeding problems from birth and poor weight gain. Metabolic investigation showed elevated plasma C3‐carnitine and C5‐OH‐carnitine. Urine analysis showed persistently elevated excretion of 3‐OH‐isovaleric acid. Biochemically, the combination of elevated C5‐OH‐carnitine and increased excretion of 3‐OH‐isovaleric acid seemed compatible with biotinidase deficiency. Supplementation with biotin was started. Biotinidase activity in plasma showed only marginally decreased activity, which was considered insufficient explanation for her clinical symptoms. Subsequent trio‐based whole exome sequencing revealed compound heterozygosity for variants in the SLC5A6 gene. Upon increasing the dosage of biotin supplementation and introduction of pantothenic acid supplementation, a striking clinical improvement was seen.

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Interaction of α-Lipoic Acid with the Human Na+/Multivitamin Transporter (hSMVT)

Cited by 24 publications

References 54 publications

Exploring Substrate Binding in the Extracellular Vestibule of MhsT by Atomistic Simulations and Markov Models

Exploring Substrate Binding in the Extracellular Vestibule of MhsT by Atomistic Simulations and Markov Models

Mutations in SLC5A6 associated with brain, immune, bone, and intestinal dysfunction in a young child

Genetic defect of the sodium‐dependent multivitamin transporter: A treatable disease, mimicking biotinidase deficiency

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