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NOXRED1

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NOXRED1
Identifiers
AliasesNOXRED1, C14orf148, NADP-dependent oxidoreductase domain containing 1, NADP dependent oxidoreductase domain containing 1
External IDsMGI: 1918525; HomoloGene: 51388; GeneCards: NOXRED1; OMA:NOXRED1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

122945

71275

Ensembl

ENSG00000165555

ENSMUSG00000072919

UniProt

Q6NXP6

Q9D3S5

RefSeq (mRNA)

NM_001113475
NM_138791
NM_001394980

NM_027744

RefSeq (protein)

NP_001106946

NP_082020

Location (UCSC)Chr 14: 77.39 – 77.42 MbChr 12: 87.27 – 87.29 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

NADP-dependent oxidoreductase domain-containing protein 1 is a protein that in humans is encoded by the NOXRED1 gene. An alias of this gene is Chromosome 14 Open Reading Frame 148 (c14orf148)[5]. This gene is located on chromosome 14, at 14q24.3.[5][6] NOXRED1 is predicted to be involved in pyrroline-5-carboxylate reductase activity as part of the L-proline biosynthetic pathway.[5] It is expressed in a wide variety of tissues at a relatively low level, including the testes, thyroid, skin, small intestine, brain, kidney, colon, and more.[5]

Gene

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NOXRED1 is coded on the minus strand of the human Chromosome 14 from nucleotides 77,394,021-77,423,523.[6] It has a total of 9 exons and 8 introns, and it spans a total of 29,502 bases.[6]

Neighborhood

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The gene neighborhood of NOXRED1 includes Transmembrane p24 TraffickingProtein Family Member 8 (TMED8), Sterile Alpha Motif Domain 15 (SAMD15), VPS33B Interacting Protein (VIPAS39), and Activator of HSP90 ATPase Activity 1 (AHSA1).

Transcripts

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NOXRED1 has three known mRNA isoforms (table 2).[7] The primary isoform is 2324 bases in length and is composed of 6 exons.[8] Isoform 2[9] and Isoform 3[10] are 1773 and 1770 nucleotides long, respectively.

Proteins

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Predicted NOXRED1 Tertiary Structure. NOXRED1 tertiary structure predicted from AlphaFold. Coils indicate alpha helices, and arrows indicate beta sheets. The color gradient represents the confidence level of the predicted structure, with dark blue being high confidence, light blue being confident, yellow being low confidence, and orange being very low confidence.

NADP-dependent oxidoreductase domain-containing protein 1 (NOXRED1) is a protein which in humans is encoded by the gene NOXRED1.[11] It is 359 residues long and has a molecular weight of ~39.9 kDa.[11] This protein is enriched in leucine residues, in comparison to other human proteins.[12] NOXRED1 is predicted to localize in the cytoplasm and perform functions involving pyrroline-5-carboxylate reductase.[7] From residues 78-189, NOXRED1 contains the conserved protein domain family pyrroline-5-carboxylate reductase (ProC).[11]

Protein isoforms

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NOXRED1 has three known protein isoforms (Table 2).[11][13][14] Isoform 1 is the largest and most abundant.[11]

Isoform Accession Number mRNA Length (nucleotides) Accession Number Protein Length (amino acids) Molecular Weight (kDa)
1 NM_001113475.3 2324 NP_001106946.1 359 39.9
2 NM_001394980.1 1773 XP_011534731.1 269 29.8
3 XM_011536429.4 1770 XP_016876458.1 234 25.9

Isoforms of NOXRED1. Information obtained from NCBI Nucleotide[15] and NCBI Protein[16] databases.

Protein level expression

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Primary Antibody Data

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ThermoFisher Scientific has developed a human polyclonal antibody targeting NOXRED1.[17] It can be used for a variety of different functions, including immunocytochemistry, immunohistochemistry, immunoprecipitation, and western blotting.[17] Additionally, the Human Protein Atlas database shows immunocytochemistry produced images of NOXRED1 within the A549, MCF-7, and U2OS cell lines[18]

In situ hybridization data

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The Allen Brain Institute shows that NOXRED1 is expressed at a moderate level throughout the Mus musculus brain[19]

Protein interactions

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Some predicted proteins that interact with the human NOXRED1 are Delta-1-pyrroline-5-carboxylate synthase and ornithine aminotransferase.[20] Delta-1-pyrroline-5-carboxylate synthase catalyzes the conversion of glutamate to delta-1-pyrroline-5-carboxylate synthase.[21] Ornithine aminotransferase is an enzyme that converts arginine and ornithine into glutamate and GABA.[22] Both of these proteins are involved in the proline biosynthesis pathway.[21][22]

Homology and evolution

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Paralogs

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NOXRED1 has three orthologs. Pyrroline-5-carboxylate reductase 1 (PYCR1), pyrroline-5-carboxylate reductase 2 (PYCR2), and pyrroline-5-carboxylate reductase 3 (PYCR3) all are also involved in the synthesis of proline from pyrroline-5-carboxylate.[23][24][25] PYCR1 is located at 17q25.3,[23] PYCR2 is located at 1q42.12,[24] and PYCR3 is located at 8q24.3.[25]

Gene Genus and Species Protein Accession Number Sequence Length (aa) % Sequence Identity to Human Protein % Sequence Similarity to Human Protein
NOXRED1 Homo sapiens NP_001106946.1 359 100 100
PYCR2 Homo sapiens NP_037460.2 320 15.4 23.3
PYCR3 Homo sapiens NP_075566.3 274 13.6 23.8
PYCR1 Homo sapiens NP_008838.2 319 13.2 20.6

Paralogs of NOXRED1. Percent sequence identity and similarity were calculated using EMBOSS Needle[26].

Phylogenetic Tree of NOXRED1 Orthologs. Created using phylogeny.fr one-click tree builder.

Orthologs

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NOXRED1 was found to be highly conserved throughout history—there are existing orthologs within mammals, aves, reptiles, amphibians, bony fish, cartilaginous fish, trichoplaxes, and some invertebrates.[27][28] Interestingly, orthologs were not able to be found in one of the three orders of amphibians—Urodela.[27] Additionally, orthologs were not able to be found in insects, fungi, protists, plants, bacteria, or archaea25.[27] Listed in a table are a list of 20 different NOXRED1 protein orthologs from a diverse array of species, including mammals, aves, reptiles, amphibians, different classes of fish, and invertebrates.

Genus and Species Common Name Taxonomic Class Taxonomic Order DOD (MYA) Accession Number AA Sequence Length % Sequence Identity to Human Protein % Sequence Similarity to Human Protein
Homo sapiens Human Mammalia Primata 0 NP_001106946.1 359 100 100
Mus musculus Mouse Mammalia Rodentia 87 NP_082020.1 366 60.6 76.9
Felis catus Cat Mammalia Carnivora 94 XP_019688936.1 381 72 79.3
Elephas maximus indicus Indian Elephant Mammalia Proboscidea 99 XP_049755695.1 384 69.4 77.2
Struthio camelus australis Southern Ostrich Aves Struthioniformes 319 XP_009673940.1 345 44 60.4
Oxyura jamaicensis Ruddy Duck Aves Anseriformes 319 XP_035184255.1 392 43.8 56.8
Pygoscelis adeliae Adélie penguin Aves Spheniscoformes 319 XP_009317781.1 323 34.4 48.8
Mauremys mutica Yellow Pond Turtle Reptilia Testudines 319 XP_044872068.1 372 47.5 65.3
Protobothrops mucrosquamatus Brown Spotted Pit Viper Reptilia Serpentes 319 XP_029139298.1 388 39.8 58.8
Gekko japonicus Japanese Gecko Reptilia Squamata 319 XP_015273827.1 403 37.6 56.6
Geotrypetes seraphini Gaboon Caecilian Amphibia Gymnophiona 353 XP_033807528.1 371 45.2 59.7
Xenopus tropicalus Western Clawed Frog Amphibia Anura 353 NP_001072734.1 344 40.9 56.5
Rana temporaria Common Frog Amphibia Anura 353 XP_040189126.1 367 36.2 52.4
Polypterus senegalus Gray bichir Actinopterygii Polypteriformes 431 XP_039598035.1 364 39.8 57.3
Danio rerio Zebrafish Actinopterygii Cypriniformes 431 XP_005169929.1 333 36.8 53.8
Rhincodon typus Whale Shark Chondrichthyes Orectolobiformes 464 XP_020369405.1 365 33.3 50.6
Petromyzon marinus Sea Lampray Hyperoartia Petromyzontiformes 599 XP_032812106.1 359 25.7 37
Strongylocentrotus purpuratus Pacific Purple Sea Urchin Echinoidea Echinoida 619 XP_011675891.2 380 28.3 47.3
Trichoplax sp. H2 Trichoplax H2 Trichoplax - 661 RDD44387.1 382 28.2 46.1
Crassostrea gigas Sea Oyster Bivalvia Ostreida 694 XP_011447367.2 366 31.6 49.7

Table 1. Orthologs of NOXRED1. Orthologs are grouped by taxonomic class and then sorted first by increasing date of divergence (MYA) and second by percent sequence identity to the human protein. Date of divergence was calculated using the pairwise divergence median time from Timetree.org.[29] Percent sequence identity and similarity were calculated using EMBOSS Needle.[26]

Function/Biochemistry

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The human NOXRED1 protein is predicted to play a role in the L-proline biosynthesis pathway.[11]

Clinical significance

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NOXRED1 has a few clinically significant associations. Chen et al., 2020 found that the variant rs8012548 (an intron variant) within NOXRED1 is significantly associated withcutaneous melanoma specific survival, meaning that patients with cutaneous melanoma who have carry rs8012548 are less likely to perish due to the disease.[30] Tabe-Bordbar et al., 2020 found that rs12890411 within intron 5 of NOXRED1 lies within an Estrogen Receptor Alpha (Erα) enhancer region.[31] This variant is an eQTL for breast cancer, and it at least partially decreases the binding affinity of the transcription factor RELA.[31] Yuan et al., 2021 predicted that NOXRED1 influences the pathogenesis of Alzheimer's disease and mild cognitive impairment by increasing oxidative stress within the limbic region.[32] Nacita et al., 2015 reported that a patient with the interstitial deletion of 14q24-14q32 exhibits developmental and neurological delays, face dysmorphology, and epilepsy.[33] Relating to the transcript, MacNair et al., 2016 found that NOXRED1 is downregulated in the motor neurons in mice with a TDP-43 mutation related to amyotrophic lateral sclerosis (ALS).[34] Relating to the protein, Vandenbrouck et al., 2016 found that NOXRED1 is found within the proteome of human spermatozoa.[35]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000165555 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000072919 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d "NOXRED1 NADP dependent oxidoreductase domain containing 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-18.
  6. ^ a b c "Human hg38 chr14:77,394,021-77,423,523 UCSC Genome Browser v437". genome.ucsc.edu. Retrieved 2022-09-28.
  7. ^ a b "AceView: Gene:C14orf148, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView". www.ncbi.nlm.nih.gov. Retrieved 2022-09-28.
  8. ^ "Homo sapiens NADP dependent oxidoreductase domain containing 1 (NOXRED1), transcript variant 1, mRNA". 2022-06-10.
  9. ^ "Homo sapiens NADP dependent oxidoreductase domain containing 1 (NOXRED1), transcript variant 2, mRNA". 2022-08-20.
  10. ^ "PREDICTED: Homo sapiens NADP dependent oxidoreductase domain containing 1 (NOXRED1), transcript variant X3, mRNA". 2022-04-05.
  11. ^ a b c d e f "NADP-dependent oxidoreductase domain-containing protein 1 isoform X1 [ - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-09-18.
  12. ^ "SAPS < Sequence Statistics < EMBL-EBI". www.ebi.ac.uk. Retrieved 2022-12-12.
  13. ^ "NADP-dependent oxidoreductase domain-containing protein 1 isoform X2 [ - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-08.
  14. ^ "NADP-dependent oxidoreductase domain-containing protein 1 isoform X3 [ - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-08.
  15. ^ "Home - Nucleotide - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-08.
  16. ^ "Home - Protein - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-08.
  17. ^ a b "Anti-NOXRED1 Antibodies | Invitrogen". www.thermofisher.com. Retrieved 2022-12-08.
  18. ^ "Subcellular - NOXRED1 - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2022-12-08.
  19. ^ "ISH Data :: Allen Brain Atlas: Mouse Brain". mouse.brain-map.org. Retrieved 2022-12-08.
  20. ^ "Pharos: Target List". pharos.nih.gov. Retrieved 2022-12-11.
  21. ^ a b "ALDH18A1 aldehyde dehydrogenase 18 family member A1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-11.
  22. ^ a b "OAT ornithine aminotransferase [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-12-11.
  23. ^ a b "PYCR1 pyrroline-5-carboxylate reductase 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-10-22.
  24. ^ a b "PYCR2 pyrroline-5-carboxylate reductase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-10-22.
  25. ^ a b "PYCR3 pyrroline-5-carboxylate reductase 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-10-22.
  26. ^ a b "EMBOSS Needle < Pairwise Sequence Alignment < EMBL-EBI". www.ebi.ac.uk. Retrieved 2022-10-22.
  27. ^ a b c "BLAST: Basic Local Alignment Search Tool". blast.ncbi.nlm.nih.gov. Retrieved 2022-10-22.
  28. ^ "NOXRED1 Gene - GeneCards | NXRD1 Protein | NXRD1 Antibody". www.genecards.org. Retrieved 2022-10-22.
  29. ^ "TimeTree :: The Timescale of Life". timetree.org. Retrieved 2022-10-22.
  30. ^ Chen K, Liu H, Liu Z, Bloomer W, Amos CI, Lee JE, et al. (November 2019). "Genetic variants in glutamine metabolic pathway genes predict cutaneous melanoma-specific survival". Molecular Carcinogenesis. 58 (11): 2091–2103. doi:10.1002/mc.23100. PMC 7504905. PMID 31435991.
  31. ^ a b abe-Bordbar S, Song YJ, Lunt BJ, Prasanth KV, Sinha S (2020-11-09). "Mechanistic analysis of enhancer sequences in the Estrogen Receptor transcriptional program". bioRxiv: 2020.11.08.373555. doi:10.1101/2020.11.08.373555. S2CID 226959729.
  32. ^ Yuan SX, Li HT, Gu Y, Sun X (June 2021). "Brain-Specific Gene Expression and Quantitative Traits Association Analysis for Mild Cognitive Impairment". Biomedicines. 9 (6): 658. doi:10.3390/biomedicines9060658. PMC 8229744. PMID 34201204.
  33. ^ Nicita F, Di Giacomo M, Palumbo O, Ferri E, Maiorani D, Vigevano F, et al. (2015-11-24). "Neurological features of 14q24-q32 interstitial deletion: report of a new case". Molecular Cytogenetics. 8 (1): 93. doi:10.1186/s13039-015-0196-6. PMC 4657200. PMID 26604985.
  34. ^ MacNair L, Xiao S, Miletic D, Ghani M, Julien JP, Keith J, et al. (January 2016). "MTHFSD and DDX58 are novel RNA-binding proteins abnormally regulated in amyotrophic lateral sclerosis". Brain. 139 (Pt 1): 86–100. doi:10.1093/brain/awv308. PMID 26525917.
  35. ^ Vandenbrouck Y, Lane L, Carapito C, Duek P, Rondel K, Bruley C, et al. (November 2016). "Looking for Missing Proteins in the Proteome of Human Spermatozoa: An Update" (PDF). Journal of Proteome Research. 15 (11): 3998–4019. doi:10.1021/acs.jproteome.6b00400. PMID 27444420.
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