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4 results on '"Endogenous metabolism"'

1. Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs.

Author

Engelhart, Darcy C, Granados, Jeffry C, Shi, Da, Saier Jr, Milton H, Baker, Michael E, Abagyan, Ruben, and Nigam, Sanjay K

Subjects
SLC22, chronic kidney disease, drug transporters, endogenous metabolism, functional subgroups, gut microbiome, remote sensing and signaling, transporters, Other Chemical Sciences, Genetics, Other Biological Sciences, Chemical Physics
Abstract

The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as "drug" transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.

Published
2020

2. Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs

Author

Engelhart, Darcy C, Granados, Jeffry C, Shi, Da, Saier, Milton H, Baker, Michael E, Abagyan, Ruben, and Nigam, Sanjay K

Subjects
Animals, Biological Transport, Gene Expression Regulation, Gene Regulatory Networks, Humans, Multigene Family, Mutation, Organic Anion Transporters, Organic Cation Transport Proteins, Signal Transduction, Substrate Specificity, Systems Biology, transporters, endogenous metabolism, functional subgroups, SLC22, remote sensing and signaling, drug transporters, gut microbiome, chronic kidney disease, Other Chemical Sciences, Genetics, Other Biological Sciences, Chemical Physics
Abstract

The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as "drug" transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory.

Published
2020

3. Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs, and Drosophila SLC22 orthologs related to OATs, OCTs, and OCTNs regulate development and responsiveness to oxidative stress

Author

Engelhart, Darcy

Subjects
Biology, drug transporters, endogenous metabolism, functional subgroups, Remote Sensing and Signaling, SLC22, transporters
Abstract

The SLC22 family of transmembrane transport proteins consists of at least 31 known members that transport organic anions (OATs), organic cations (OCTs) and zwitterions (OCTNs). Despite their interaction with many endogenous metabolites and signaling molecules, many of these transporters are referred to as “drug” transporters since they facilitate the movement of pharmaceutical drugs. However, their evolution and conservation as a group underscores key endogenous functions. Chapter 1 suggests a re-designation of SLC22 into nine subclades with four new, functional subclades arising out of the previously defined Oat subclade - referred to as Oat subgroups. These new Oat subgroups are: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, SLC22A25 plus the rodent expansion of slc22a19, and slc22a26-30). We also propose the reclassification of SLC22A16 into the preexisting OCTN subclade (SLC22A4, SLC22A5, and slc22a21) and the renaming of the Oct-related subclade, which now contains only SLC22A15, to the Octn-related subclade. Due to the functional similarities between the Drosophila melanogaster (fruit fly) hindgut and Malpighian tubules and the human intestines and kidneys, where most, if not all SLC22 family members can be localized, we are assessing the functionality of SLC22 transport proteins using flies as a model organism. Chapter 2 explores orthologous relationships between D. melanogaster transporters and their human counterparts. It also assesses fly transporters for their role in management of oxidative stress.

Published
2020

4. Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs, and Drosophila SLC22 orthologs related to OATs, OCTs, and OCTNs regulate development and responsiveness to oxidative stress

Author

Engelhart, Darcy

Subjects
Biology, drug transporters, endogenous metabolism, functional subgroups, Remote Sensing and Signaling, SLC22, transporters
Abstract

The SLC22 family of transmembrane transport proteins consists of at least 31 known members that transport organic anions (OATs), organic cations (OCTs) and zwitterions (OCTNs). Despite their interaction with many endogenous metabolites and signaling molecules, many of these transporters are referred to as “drug” transporters since they facilitate the movement of pharmaceutical drugs. However, their evolution and conservation as a group underscores key endogenous functions. Chapter 1 suggests a re-designation of SLC22 into nine subclades with four new, functional subclades arising out of the previously defined Oat subclade - referred to as Oat subgroups. These new Oat subgroups are: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, SLC22A25 plus the rodent expansion of slc22a19, and slc22a26-30). We also propose the reclassification of SLC22A16 into the preexisting OCTN subclade (SLC22A4, SLC22A5, and slc22a21) and the renaming of the Oct-related subclade, which now contains only SLC22A15, to the Octn-related subclade. Due to the functional similarities between the Drosophila melanogaster (fruit fly) hindgut and Malpighian tubules and the human intestines and kidneys, where most, if not all SLC22 family members can be localized, we are assessing the functionality of SLC22 transport proteins using flies as a model organism. Chapter 2 explores orthologous relationships between D. melanogaster transporters and their human counterparts. It also assesses fly transporters for their role in management of oxidative stress.

Published
2020

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