Table 1.

Classification and characteristics of bacterial sialic acid transporters

Family ID*	Pfam†	Updated name	Components‡	Alternative name§	Experimental confirmation||	Energization¶	Specificity#	Reference system∗∗	UniProt†	PDB†	TCDB†
ST1	MFS_1 PF07690	NanT	Single TMD (14 TMH)	–	1985 [25]	H+ [28]	Neu5Ac	Escherichia coli	P41036	–	2.A.1.12.1
	MFS_1 PF07690	NanX	Single TMD (12 TMH)	YjhB, ORF425 [10, 26, 51, 52, 92]	2020 [51, 52]	H+	2,7-Anhydro-Neu5Ac Neu5Ac2en	Escherichia coli	P39352	–	–
ST2	DctP PF03480	SiaPQM	SiaP (SBP), SiaQM (TMD1+TMD2) or SiaP (SBP), SiaQ (TMD1), SiaM (TMD2)	SiaPT, NanPU, NeuT [19, 42, 86, 93–97]	2005 [15, 93]	Na+ [28, 36]	Neu5Ac	Haemophilus influenzae, Vibrio cholerae	P44542, Q9KR64	2CEX††, 4MAG††	2.A.56.1.3, 2.A.56.1.6
ST3	SBP_bac_5 PF00496	SatABCD	SatA (SBP), SatB (TMD1), SatC (TMD2+NBD2), SatD (NBD1)	SAT, SiaEFGI, NanBCDF, NanABC2 [13, 76, 80, 86]	2005 [38]	ATP	Neu5Ac	Haemophilus ducreyi	Q7VL18	5ZA4, 5Z99, 5YYB	–
ST4	MFS_1 PF07690	NanZ	Single TMD (12 TMH)	NanT [30, 31]	2009 [30]	H+	Neu5Ac	Bacteroides fragilis, Tannerella forsythia	Q5LEN6, A0A1D3USD0	–	–
ST5	SSF PF00474	SiaT	Single TMD (13 TMH)	STM1128, NanT, NanV, NanX, NanP [4, 29, 48, 73, 86, 98, 99]	2010 [29]	Na+ [22, 29, 47]	Neu5Ac	Proteus mirabilis, Salmonella typhimurium, Staphylococcus aureus	B4EZY7, Q8ZQ35, Q2G161§§	5NV9, 5NVA	2.A.21.3.10‡‡
	SSF PF00474	SiaX	Single TMD (13 TMH)	NanT [16, 73]	2013 [16]	Na+	Neu5Ac 2,7-anhydro-Neu5Ac(?) Neu5Ac2en(?)	Clostridiodes difficile, Streptococcus pneumoniae	Q185B4, A0A0H2UQE5	–	–
	SSF PF00474	SiaF	CPM+TMD (13 TMH)	–	nc	Na+	Neu5Ac(?)	Alistipes timonensis	A0A1H4AP10	–	–
ST6	SBP_bac_1 PF01547	SatEFG	SatE (SBP), SatF (TMD1), SatG (TMD2), SatH (NBD)||||	SatABC, NanUVW, SAT3, NanT, NanABC [13, 17, 44–46, 81, 86]	2011 [17]	ATP	Neu5Ac	Streptococcus pneumoniae	A0A0H2ZL68	–	–
ST7	SBP_bac_1 PF01547	SatXYZ	SatX (SBP), SatY (TMD1), SatZ (TMD2), SatW (NBD)||||	SAT2 [14]	2019 [14]	ATP	2,7-Anhydro-Neu5Ac	Ruminococcus gnavus	A7B561	–	–
ST8	MFS_2 PF13347	NanG	Single TMD (11 TMH)	GPH [51]	nc	H+ or Na+	2,7-Anhydro-Neu5Ac(?)	Lactobacillus salivarius	A0A1V9QLX9	–	–

*ST families are as defined in Figs 2 and 3. ST families are ordered by date of experimental confirmation (see footnote ||). ST1 and ST5 have been further subdivided to reflect the functional and phylogenetic differences among clades.

†In the case of SBP-dependent transporters Pfam, UniProt, PDB and TCDB identifiers all refer to the those of the SBP component, consistent with the methodology used for the phylogenetic analyses (see Methods).

‡SBP, solute-binding protein; TMH, transmembrane helix; TMD, transmembrane domain; NBD, nucleotide binding domain; CPM, cyclically permutated mutarotase (NanM-domain). For single component transporters, we indicate the number of TMHs to emphasize structural differences.

§We list here all the names used for ST uptake systems in the literature. These include locus tags used before functional confirmation, identical names used for different transporters, different names used for the same transporter, and group identifiers.

||For each ST family, we include here only the date when function in sialic acid uptake was first demonstrated. Additional dates are used in the case of transporters of distinct clades (see footnote *). nc, Not confirmed.

¶Mode of energization is predicted from the Pfam of each ST family. References are included for those cases where the identity of the coupling ion used by secondary transporters has been demonstrated.

#Some Neu5Ac-specific transporters can also transport Neu5Gc and/or KDN – these details are not included here for the sake of simplicity. '(?)' means that the substrate is not confirmed and is primarily predicted based on gene clusters analysis.

∗∗Organism(s) of origin for the first-discovered and/or best-characterized transporters of the family. Please note that, while not indicated here, some transporters may be limited to specific strains of a species. In the case of the uncharacterized transporters in this table, we use Alistipes timonensis for SiaF (ST5), as this organism’s growth is stimulated by Neu5Ac [73], while we use Lactobacillus salivarius for NanG (ST8), as this is the only example to date where the nanG gene maps to a complete nan cluster (Fig. S12).

††Several structures of SiaP have been solved including orthologues from different organisms, complexes with different substrates, and also mutant proteins. The complete list includes: 2CEY, 2CEX, 3B50, 2V4C, 2WX9, 2WYP, 2WYK, 2XA5, 2XWV, 2XWO, 2XXK, 2XWI, 2XWK, 4MAG, 4MMP, 4MNP, 5LTC, 6H76, 6H75.

‡‡TCDB [100] lists, under other names, two further SiaT proteins: 2.A.21.3.7 (reported [29] but uncharacterized, from Aliivibrio fischeri) and 2.A.21.3.20 (genetically characterized [48], from Lactobacillus sakei). Both feature in our phylogenetic analysis (Fig. 4).

§§The best-characterized SiaT orthologue from S. aureus comes from strain RF122 [22] (locus tag SAB0251c), which does not possess a UniProt entry. We here replace it with the entry for strain NCTC 8325, which differs by a single residue.

||||ST6 and ST7 transporters generally rely on conserved, multitasking NBD proteins such as MsmK for function [44]. A minority of clusters do include a gene coding for NBD linked to ST6 and ST7 genes (see Figs S10 and S11), and we here propose names for these additional components.