Nicotinamide ribonucleoside uptake transporters

Last updated
Identifiers
SymbolPnuC
Pfam PF04973
TCDB 4.B.1
OPM superfamily 377
OPM protein 4qtn

The Nicotinamide Ribonucleoside (NR) Uptake Permease (PnuC) Family (TC# 4.B.1) is a family of transmembrane transporters that is part of the TOG superfamily. [1] Close PnuC homologues are found in a wide range of Gram-negative and Gram-positive bacteria, archaea and eukaryotes. [2]

Contents

Function

PnuC of Salmonella typhimurium and Haemophilus influenzae are believed to function cooperatively with NadR homologues, multifunctional proteins that together with PnuC, participate in NR phosphorylation, transport and transcriptional regulation. [3] [4] [5] NadR, a cytoplasmic protein that is partly membrane associated, contains one well conserved and one poorly conserved mononucleotide-binding consensus sequence (G-X4 GKS). It drives transport and may render transport responsive to internal pyridine nucleotide levels. While its N-terminal half functions as a repressor, its C-terminal half functions as an NR kinase in a putative group translocation process. [6]

PnuC of Haemophilus influenzae

The H. influenzae homologue has been shown to transport NR from the periplasm into the cytoplasm. Phosphorylation of NR by NadR is required for NR uptake. The ribonucleoside kinase (RNK) domain has both Walker A and Walker B motifs, responsible for ATP binding and phosphoryl transfer. In addition, a proposed LID domain was identified in RNK. LID domains have been found in other kinases, and these domains are regions which are able to move after substrate binding. They are responsible for coordination of three distinct conformations, an open state in the absence of substrate, a partially closed state after substrate binding, and a fully closed state when both substrates are present.

In H. influenzae, NR enters the NAD+ resynthesis pathway after phosphorylation to NMN, and subsequently, NAD+ is synthesized from NMN and ATP via an NMN adenylyl transferase activity. [7] [8] NadR represents a multifunctional regulator/enzyme complex able to integrate several functions, such as enzymatic catalysis, transport, and transcriptional regulatory activities.

Other constituents required for uptake

The components of the H. influenzae pathway necessary for NAD+, NMN, and NR uptake have been determined. Merdanovic et al. characterized two enzymes, an outer membrane nucleotide phosphatase, and an NAD+ nucleotidase (NadN) located in the periplasm. [9] [10] [11] They showed that NAD+ and NMN cross the outer membrane mainly via the OmpP2 porin. [12]

Only NR can be utilized by the PnuC transport system located in the inner membrane. [13] [14] The pnuC gene product is the protein that is responsible for the main flow of the NR substrate into the cytoplasm. The study of Merdanovic et al. suggests that the RNK activity of NadR determines NR transport and is negatively regulated by cytoplasmic NAD+ feedback inhibition. Therefore, NR uptake is under NadR feedback control. [4]

ATP, not the proton motive force, appears to be required for NR uptake. Thus, the driving force for NR uptake via PnuC is NR phosphorylation by NadR. A concerted group translocation mechanism can be considered whereby NadR facilitates the dissociation of NR from PnuC by phosphorylating it to NMN, thus preventing efflux of NR.

Transport reaction

The proposed transport reaction catalyzed by PnuC and NadR is: [2]

NR (out) + ATP (in) → NMN (in) + ADP (in).

Structure

PnuC of Salmonella typhimurium and Haemophilus influenzae are integral membrane proteins, 239 and 226 amino acyl residues (aas) in length, respectively, with 7 putative transmembrane α-helical segments.

The structure of NadR has been determined. [15] Mutations in the nadR gene which interfere with NR uptake occur in the C-terminal part of NadR. [16] A helix-turn-helix DNA binding domain present in NadR of S. enterica serovar Typhimurium [16] could not be found in the NadR homologue of H. influenzae. Therefore, it was proposed that in H. influenzae NadR has no regulatory function at the transcriptional level. [7] The structures of the human NR kinase 1 (2QL6_P) with nucleotide and nucleoside substrates bound have been solved. [17] It is structurally similar to Rossmann fold metabolite kinases.

PnuC has been shown to resemble SWEET porters in overall fold, [18] supporting the conclusion that these two families are members of the TOG superfamily. [1]

Crystal structures

NadR Protein from H. influenzae PDB: 1LW7 ​

NR transporter PnuC PDB: 4QTN ​

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References

  1. 1 2 Yee DC, Shlykov MA, Västermark A, Reddy VS, Arora S, Sun EI, Saier MH (November 2013). "The transporter-opsin-G protein-coupled receptor (TOG) superfamily". The FEBS Journal. 280 (22): 5780–800. doi:10.1111/febs.12499. PMC   3832197 . PMID   23981446.
  2. 1 2 Saier, MH Jr. "4.B.1 The Nicotinamide Ribonucleoside (NR) Uptake Permease (PnuC) Family". Transporter Classification Database. Saier Lab Bioinformatics Group / SDSC.
  3. ↑ Foster JW, Park YK, Penfound T, Fenger T, Spector MP (August 1990). "Regulation of NAD metabolism in Salmonella typhimurium: molecular sequence analysis of the bifunctional nadR regulator and the nadA-pnuC operon". Journal of Bacteriology. 172 (8): 4187–96. doi:10.1128/jb.172.8.4187-4196.1990. PMC   213241 . PMID   2198247.
  4. 1 2 Merdanovic M, Sauer E, Reidl J (July 2005). "Coupling of NAD+ biosynthesis and nicotinamide ribosyl transport: characterization of NadR ribonucleotide kinase mutants of Haemophilus influenzae". Journal of Bacteriology. 187 (13): 4410–20. doi:10.1128/JB.187.13.4410-4420.2005. PMC   1151767 . PMID   15968050.
  5. ↑ Penfound T, Foster JW (January 1999). "NAD-dependent DNA-binding activity of the bifunctional NadR regulator of Salmonella typhimurium". Journal of Bacteriology. 181 (2): 648–55. doi:10.1128/JB.181.2.648-655.1999. PMC   93422 . PMID   9882682.
  6. ↑ Mitchell P, Moyle J (August 1958). "Group-translocation: a consequence of enzyme-catalysed group-transfer". Nature. 182 (4632): 372–3. Bibcode:1958Natur.182..372M. doi:10.1038/182372a0. PMID   13577842. S2CID   4261342.
  7. 1 2 Kurnasov OV, Polanuyer BM, Ananta S, Sloutsky R, Tam A, Gerdes SY, Osterman AL (December 2002). "Ribosylnicotinamide kinase domain of NadR protein: identification and implications in NAD biosynthesis". Journal of Bacteriology. 184 (24): 6906–17. doi:10.1128/jb.184.24.6906-6917.2002. PMC   135457 . PMID   12446641.
  8. ↑ Cynamon MH, Sorg TB, Patapow A (October 1988). "Utilization and metabolism of NAD by Haemophilus parainfluenzae". Journal of General Microbiology. 134 (10): 2789–99. doi: 10.1099/00221287-134-10-2789 . PMID   3254936.
  9. ↑ Kemmer G, Reilly TJ, Schmidt-Brauns J, Zlotnik GW, Green BA, Fiske MJ, Herbert M, Kraiss A, Schlör S, Smith A, Reidl J (July 2001). "NadN and e (P4) are essential for utilization of NAD and nicotinamide mononucleotide but not nicotinamide riboside in Haemophilus influenzae". Journal of Bacteriology. 183 (13): 3974–81. doi:10.1128/JB.183.13.3974-3981.2001. PMC   95280 . PMID   11395461.
  10. ↑ Reidl J, Schlör S, Kraiss A, Schmidt-Brauns J, Kemmer G, Soleva E (March 2000). "NADP and NAD utilization in Haemophilus influenzae". Molecular Microbiology. 35 (6): 1573–81. doi:10.1046/j.1365-2958.2000.01829.x. PMID   10760156. S2CID   29776509.
  11. ↑ Schmidt-Brauns J, Herbert M, Kemmer G, Kraiss A, Schlör S, Reidl J (August 2001). "Is a NAD pyrophosphatase activity necessary for Haemophilus influenzae type b multiplication in the blood stream?". International Journal of Medical Microbiology. 291 (3): 219–25. doi:10.1078/1438-4221-00122. PMID   11554562.
  12. ↑ Andersen C, Maier E, Kemmer G, Blass J, Hilpert AK, Benz R, Reidl J (July 2003). "Porin OmpP2 of Haemophilus influenzae shows specificity for nicotinamide-derived nucleotide substrates". The Journal of Biological Chemistry. 278 (27): 24269–76. doi: 10.1074/jbc.M213087200 . PMID   12695515.
  13. ↑ Herbert M, Sauer E, Smethurst G, Kraiss A, Hilpert AK, Reidl J (September 2003). "Nicotinamide ribosyl uptake mutants in Haemophilus influenzae". Infection and Immunity. 71 (9): 5398–401. doi:10.1128/iai.71.9.5398-5401.2003. PMC   187334 . PMID   12933892.
  14. ↑ Sauer E, Merdanovic M, Mortimer AP, Bringmann G, Reidl J (December 2004). "PnuC and the utilization of the nicotinamide riboside analog 3-aminopyridine in Haemophilus influenzae". Antimicrobial Agents and Chemotherapy. 48 (12): 4532–41. doi:10.1128/AAC.48.12.4532-4541.2004. PMC   529221 . PMID   15561822.
  15. ↑ Singh SK, Kurnasov OV, Chen B, Robinson H, Grishin NV, Osterman AL, Zhang H (September 2002). "Crystal structure of Haemophilus influenzae NadR protein. A bifunctional enzyme endowed with NMN adenyltransferase and ribosylnicotinimide kinase activities". The Journal of Biological Chemistry. 277 (36): 33291–9. doi: 10.1074/jbc.M204368200 . PMID   12068016.
  16. 1 2 Foster JW, Penfound T (September 1993). "The bifunctional NadR regulator of Salmonella typhimurium: location of regions involved with DNA binding, nucleotide transport and intramolecular communication". FEMS Microbiology Letters. 112 (2): 179–83. doi: 10.1016/0378-1097(93)90161-t . PMID   8405960.
  17. ↑ Tempel W, Rabeh WM, Bogan KL, Belenky P, Wojcik M, Seidle HF, Nedyalkova L, Yang T, Sauve AA, Park HW, Brenner C (October 2007). "Nicotinamide riboside kinase structures reveal new pathways to NAD+". PLOS Biology. 5 (10): e263. doi:10.1371/journal.pbio.0050263. PMC   1994991 . PMID   17914902.
  18. ↑ Jaehme M, Guskov A, Slotboom DJ (February 2016). "Pnu Transporters: Ain't They SWEET?" (PDF). Trends in Biochemical Sciences. 41 (2): 117–118. doi:10.1016/j.tibs.2015.11.013. PMID   26692123.
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