Thyroid hormone transport across L-type amino acid transporters: What can molecular modelling tell us?

Krause, Gerd; Hinz, Katrin Manuela

doi:10.1016/j.mce.2017.03.018

Cited by 26 publications

(16 citation statements)

References 51 publications

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“…Additionally, a recent study demonstrated that the meta -substituted halogens exhibit an inhibition trend I > Br > Cl > F in phenylalanine and Br > Cl = F > I in tyrosine [28], possibly indicating halogen interactions in these analogs with the binding site residues of LAT1. Interestingly, Krause et al have alleged halogen interactions that can justify the high affinity of T 3 and 3,3′-T 2 in LAT2 [73]. Both LAT1 and LAT2 have aromatic and hydrophilic residues in their binding site that can function as halogen bond acceptors and hydrogen bond donors to the halogens.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods

Singh

Scalise

Galluccio

et al. 2018

IJMS

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The large neutral amino acid transporter 1 (LAT1) is a promising anticancer target that is required for the cellular uptake of essential amino acids that serve as building blocks for cancer growth and proliferation. Here, we report a structure-based approach to identify chemically diverse and potent inhibitors of LAT1. First, a homology model of LAT1 that is based on the atomic structures of the prokaryotic homologs was constructed. Molecular docking of nitrogen mustards (NMs) with a wide range of affinity allowed for deriving a common binding mode that could explain the structure−activity relationship pattern in NMs. Subsequently, validated binding hypotheses were subjected to molecular dynamics simulation, which allowed for extracting a set of dynamic pharmacophores. Finally, a library of ~1.1 million molecules was virtually screened against these pharmacophores, followed by docking. Biological testing of the 30 top-ranked hits revealed 13 actives, with the best compound showing an IC50 value in the sub-μM range.

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Section: Discussionmentioning

confidence: 99%

Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods

Singh

Scalise

Galluccio

et al. 2018

IJMS

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“…That effect of 3,5-T2 on hepatic metabolism, especially lipid metabolism, might be due to a remarkable accumulation of 3,5-T2 in the liver, which so far had not been reported in appropriate experimental paradigms. Whether 3,5-T2 accumulation is an issue of increased import or decreased export remains to be studied, as the classical transporters for thyroid hormones such as MCT8, MCT10, OATP, and LATs typically show low transport activity for 3,5-T2 compared to the other T4, T3, or 3,3 ′ -T2, as the structural isomer of 3,5-T2 (101,102). Considering these controversial and-with respect to species analyzed and models employed-conflictings observations, the initial enthusiasm of developing 3,5-T2 related agents as anti-steatotic drugs, devoid of thyromimetic activity and side effects, remains questionable, and more research is definitely needed if this path should be further taken.…”

Section: 5-t2 Accumulates In Tissues and Might Act By Intracrine Mementioning

confidence: 99%

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

et al. 2020

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Structural formula of the "Janus-faced" THM 3,5-diiodo-L-thyronine (left), which has the same 3,5-iodine substitution pattern as its putative precursors L-T4 and L-T3 at the tyrosyl-ring, but lacks the iodine substitution in 3 ′-position of the phenolic ring which is essential for binding classical T3-receptors and conveying canonical and non-canonical thyromimetic effects. The roman god Janus symbolized "duality" and "jani" were ceremonial gateways in ancient Rome typically used for symbolically auspicious entrances or exits. Janus-face (right) source: This image comes from the 4th edition of Meyers Konversationslexikon (1885-90). The copyrights have expired and this image is in the public domain. Wikimedia, Meyers_b9_s0153_b1.png. HYPOTHESES AND THEORY a. 3,5-T2 is an endogenous metabolite of thyroid hormones T4 and T3 b. 3,5-T2 might represent the precursor of 3-iodothyronamine c. 3,5-T2 acts like T3 via canonical activation of T3 receptors albeit with lower potency d. 3,5-T2 exerts actions distinct from those of thyromimetically active T3 i) via mitochondrial targets ii) by its intrahepatic accumulation iii) by its intracrine mode of action e. 3,5-T2 formation and action might be altered in patients on T4 replacement therapy and causes adverse effects if abused.

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“…Although originally discovered in Na + coupled symporters 22 , the same fold was also found associated with a sodium independent amino acid symporter ApcT 23 and the amino acid exchangers AdiC 24 and GadC 25 . AdiC, an arginine-agmatine exchanger, has been used as a model system for understanding amino acid recognition in the large-neutral amino acid transporter, LAT-1 (SLC7A5) 26 and -2 (SLC7A8) 27 , 28 . However, neither AdiC nor the other currently reported structures from APC family members share high sequence identity with the mammalian CATs, leaving fundamental questions concerning amino acid recognition, selectivity and transport mechanism unanswered.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for amino acid transport by the CAT family of SLC7 transporters

2018

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Amino acids play essential roles in cell biology as regulators of metabolic pathways. Arginine in particular is a major signalling molecule inside the cell, being a precursor for both l-ornithine and nitric oxide (NO) synthesis and a key regulator of the mTORC1 pathway. In mammals, cellular arginine availability is determined by members of the solute carrier (SLC) 7 family of cationic amino acid transporters. Whereas CAT-1 functions to supply cationic amino acids for cellular metabolism, CAT-2A and -2B are required for macrophage activation and play important roles in regulating inflammation. Here, we present the crystal structure of a close homologue of the mammalian CAT transporters that reveals how these proteins specifically recognise arginine. Our structural and functional data provide a model for cationic amino acid transport in mammalian cells and reveals mechanistic insights into proton-coupled, sodium-independent amino acid transport in the wider APC superfamily.

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Thyroid hormone transport across L-type amino acid transporters: What can molecular modelling tell us?

Cited by 26 publications

References 51 publications

Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods

Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

Structural basis for amino acid transport by the CAT family of SLC7 transporters

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