A bioinformatic analysis of zinc transporters in intestinal Lactobacillaceae

Uyen Huynh; Hazel N Nguyen; Brittany K Trinh; Joanna Elhaj; Melissa L Zastrow

doi:10.1093/mtomcs/mfad044

. 2023 Jul 18;15(8):mfad044. doi: 10.1093/mtomcs/mfad044

A bioinformatic analysis of zinc transporters in intestinal Lactobacillaceae

Uyen Huynh ¹, Hazel N Nguyen ², Brittany K Trinh ³, Joanna Elhaj ⁴, Melissa L Zastrow ^5,^✉

PMCID: PMC10391621 PMID: 37463796

Abstract

As the second most abundant transition element and a crucial cofactor for many proteins, zinc is essential for the survival of all living organisms. To maintain required zinc levels and prevent toxic overload, cells and organisms have a collection of metal transport proteins for uptake and efflux of zinc. In bacteria, metal transport proteins are well defined for model organisms and many pathogens, but fewer studies have explored metal transport proteins, including those for zinc, in commensal bacteria from the gut microbiota. The healthy human gut microbiota comprises hundreds of species and among these, bacteria from the Lactobacillaceae family are well documented to have various beneficial effects on health. Furthermore, changes in dietary metal intake, such as for zinc and iron, are frequently correlated with changes in abundance of Lactobacillaceae. Few studies have explored zinc requirements and zinc homeostasis mechanisms in Lactobacillaceae, however. Here we applied a bioinformatics approach to identify and compare predicted zinc uptake and efflux proteins in several Lactobacillaceae genera of intestinal relevance. Few Lactobacillaceae had zinc transporters currently annotated in proteomes retrieved from the UniProt database, but protein sequence-based homology searches revealed that high-affinity ABC transporter genes are likely common, albeit with genus-specific domain features. P-type ATPase transporters are probably also common and some Lactobacillaceae genera code for predicted zinc efflux cation diffusion facilitators. This analysis confirms that Lactobacillaceae harbor genes for various zinc transporter homologs, and provides a foundation for systematic experimental studies to elucidate zinc homeostasis mechanisms in these bacteria.

Keywords: zinc, zinc transporters, microbiota, zinc homeostasis, Lactobacillaceae bacteria, metalloproteome

Graphical Abstract

Introduction

Divalent zinc ions are vital for cellular physiology. As a redox stable element, Zn²⁺ serves catalytic, structural, and regulatory functions in many proteins. Cells utilize various regulatory mechanisms to ensure adequate zinc levels for life and exclude excess zinc ions.¹ This regulation is important because many proteins require zinc to function properly yet excess Zn²⁺ ions can bind adventitiously to protein sites, causing mis-metalation and potentially inhibiting vital processes.^2,3 Because zinc is also necessary for the virulence of several pathogenic bacteria,^4,5 host-mediated Zn²⁺ withholding is an important component of nutritional immunity that can restrict zinc bioavailability and limit the growth of these organisms.⁶ There is also evidence that host-imposed zinc overload is toxic to bacterial pathogens.^7–9 Although most studies have focused on the mechanisms by which bacterial pathogens respond to metal deprivation or intoxication, those same changes in zinc bioavailability can also affect resident microorganisms. In the gastrointestinal tract (GIT), it is now well documented that the host diet alters the composition of the gut microbiota.^10,11 In particular, many studies have linked changes in dietary metals, including zinc, with changes in the relative abundance of various intestinal bacteria.^12–16 These changes have also been correlated with changes to infection susceptibility or to intestinal diseases.^13,17–19 Uncovering the mechanisms used by commensal bacteria to respond to changes in metal nutrients is a relatively recent area of interest.

Among intestinal bacteria, the Lactobacillaceae family is frequently affected by varied zinc levels.¹⁶ Lactobacillaceae are a diverse family of gram-positive lactic acid bacteria found in the GIT of many mammals.^20,21 These bacteria frequently have beneficial effects on intestinal health and changes in their abundance are often correlated with intestinal diseases and increased susceptibility to infection.^20,22,23 Lactic acid bacteria make up an estimated 0.01–1.8% of the gut bacterial community, although they are more prevalent in the human small intestine than the large intestine.^24–26 Lactobacillaceae have several documented beneficial effects ranging from protecting the host from pathogenic organisms to stimulating the immune system.^23,27 Due to these benefits and that they are generally regarded as safe, Lactobacillaceae are frequently used in probiotic formulations. Beyond the GIT, Lactobacillaceae are broadly found in various fermented foods and plants.²⁸ Although many Lactobacillaceae can be found transiently in the GIT, some genera are considered to be “host-adapted” and several species may be considered to permanently colonize the GIT.^21,29 Zinc supplementation or excess is frequently, though not always, correlated with decreases in Lactobacillaceae abundance across several animal models.¹⁶ These changes in abundance are often measured on the family level, but studies that have investigated changes at the species level have observed opposite effects for different Lactobacillaceae species in response to zinc.^30,31 These effects are not yet predictable, as very little is known about zinc requirements and zinc transporters in Lactobacillaceae.¹⁶

Few studies have investigated zinc homeostasis in Lactobacillaceae. Some studies have investigated how different zinc concentrations affect growth of some species, finding that the effects can vary between species, but the underlying mechanisms have not yet been described.^32–34 Thus far, no zinc regulatory proteins or transporters have been identified or experimentally confirmed in intestinal Lactobacillaceae.¹⁶ Genomes have now been reported and annotated for many species of Lactobacillaceae. Given that zinc transporters are well documented in several bacterial model organisms and pathogens,^9,35–37 here we aimed to apply a bioinformatics approach to search the proteomes of several intestinal Lactobacillaceae and predict zinc transporters (Scheme 1). First, we analysed the complete proteomes of several well-studied intestinal Lactobacillaceae species retrieved from the UniProt Knowledgebase (UniProtKB). After finding that there are few zinc transporters currently annotated on UniProtKB for these Lactobacillaceae species, we carried out a protein sequence-based (BLASTP) search for bacterial zinc transporter sequences across several intestinally relevant Lactobacillaceae genera. Here we used literature and the National Center for Biotechnology Information (NCBI) and UniProt databases to compile a set of bacterial zinc transport proteins, then we performed BLASTP searches using this set of proteins against the NCBI non-redundant database of proteins found in seven intestinally relevant Lactobacillaceae genera. A comparison of currently annotated zinc transporters on UniProt with those predicted from the BLASTP search for several of the most well-studied Lactobacillaceae strains reveals that current annotated data is likely incomplete. Furthermore, BLASTP searches allow us to predict zinc transporters in most Lactobacillaceae searched, including high-affinity zinc uptake ATP-binding cassette (ABC) transporters and several P-type ATPase transporters, as well as cation diffusion facilitators (CDFs) in some genera. Conversely, several strains of Lactobacillaceae did not have any zinc transporters annotated or predicted on UniProtKB, and several others only had transporters annotated that may be involved in secondary zinc uptake (e.g. the manganese transporter MntH).³⁸ In addition to identifying several sequences similar to known zinc transporters, an operon analysis of the predicted ABC transporter domains found in several strains revealed novel permease sequences in the Limosilactobacillus genus and a possible unique zinc substrate-binding domain in Lactobacillus delbruecki ATCC 11842. This bioinformatic analysis and compilation of predicted zinc transporters provides a foundation for studying zinc homeostasis in Lactobacillaceae, particularly for commensal and probiotic organisms in the gut microbiota, and could lead to a better understanding of and ability to modulate how dietary zinc impacts health through the gut microbiota. Furthermore, this work provides insight to the zinc transport machinery likely present in several species within the Lactobacillaceae family and sets a solid foundation for future experimental studies.

Analysis of Lactobacillaceae metalloproteome annotations from UniProtKB

There are no experimentally characterized zinc transporters from the Lactobacillaceae family. To gain insight into the annotated zinc transporters and, more broadly, the annotated metalloproteomes in Lactobacillaceae, we analysed the complete proteomes of intestinal Lactobacillaceae species retrieved from UniProtKB (Scheme 1). Annotations on UniProtKB include both experimentally verified proteins and those predicted by sequence homology. The complete proteome for each organism is the entire set of proteins reported on UniProtKB.^39,40 The Lactobacillaceae family comprises 33 genera, including 23 genera that were formerly included in the recently split Lactobacillus genus.^21,41 Lactobacillaceae are a family of lactic acid bacteria that includes homofermentative and heterofermentative organisms and does not include any pathogenic or opportunistic species. Because of the size and diversity of the entire family, here we focused on investigating intestinal Lactobacillaceae genera with species well known to colonize permanently in the GIT, which are used in probiotic formulations, have potential probiotic effects, or are found in food. These genera include Lactobacillus, Limosilactobacillus, Lacticaseibacillus, Ligilactobacillus, Lactiplantibacillus, Latilactobacillus, and Levilactobacillus (Supplementary Table S1).²¹ For each genus, representative species were selected based on how gut-relevant and well studied they are compared to other species in the same genus (Supplementary Table S1).

A keyword-based search was performed on the proteins annotated in UniProtKB for each proteome to determine the metalloproteome composition and how well curated it is (Supplementary methods). Analysis of the annotated proteins in UniProtKB revealed that many Lactobacillaceae species are not as well studied and that their proteomes are not as highly curated as model organisms Escherichia coli K12 and Bacillus subtilis subsp. subtilis str. 168 (Supplementary Fig. S1; Supplementary Table S2). Over 80% of the annotated proteins in the proteomes of each intestinal Lactobacillaceae species are unreviewed (Supplementary Table S2). By comparison, only ∼2% of proteins in the annotated E. coli K12 proteome remain unreviewed and ∼50% of the proteins in the annotated B. subtilis 168 proteome are unreviewed. Around 8000 total proteins are reported for B. subtilis 168 compared to ∼4000 for E. coli K12 and only ∼2000 for most of the Lactobacillaceae species. Unreviewed proteins are typically those predicted by homology or evidence at the transcript level only and are automatically annotated and classified from computationally analysed records. Reviewed proteins are manually annotated by the UniProtKB expert biocuration team using experimental results from literature and computational analysis.^42,43 Uncharacterized proteins, on the other hand, are known or unknown proteins designated as uncharacterized in the protein name by UniProtKB, and may be reviewed or unreviewed. Around 15–25% of the proteomes of E. coli K12, B. subtilis 168, and most of the Lactobacillaceae species investigated here remain uncharacterized, except Lactiplantibacillus plantarum WCFS1 (10%).

The annotated metalloproteomes of Lactobacillaceae are distinct from those of E. coli and B. subtilis (Fig. 1A; Supplementary Table S3). Iron-associated proteins comprise 8% of the E. coli K12 proteome but less than 1.7% for the Lactobacillaceae species analysed here. Although the annotated iron-associated proteins comprise the largest anticipated metal-associated protein fraction for E. coli K12, annotated zinc-associated proteins comprise the largest identified or predicted metal-associated protein fraction for the Lactobacillaceae species studied here (∼2–3%). This result is consistent with prior studies showing that many Lactobacillaceae have low iron requirements, although there may be iron proteins that have not been annotated or yet discovered.^16,44–46 Lactobacillaceae species are known to take up high concentrations of manganese compared to species like E. coli.^47,48 Although the annotated metalloproteomes show that few manganese-associated proteins have been identified or predicted in Lactobacillaceae species (<1% of the total proteomes compared to 2% for E. coli K12), manganese complexed with non-proteinaceous metabolites or small molecules like orthophosphate, lactate, and malate has been shown to have antioxidant activity in a variety of organisms.^49,50 Unknown or unidentified metal-associated proteins take up 10% of the E. coli K12 proteome and 5–7% of the proteomes for the Lactobacillaceae species analysed here.

An analysis of the predicted functions for annotated zinc-associated proteins was also carried out (Supplementary Methods, Supplementary Tables S5–S6, Fig. 1B). Here, annotated zinc uptake transporters were found in several but not all species of Lactobacillaceae analysed. Efflux transporters and regulators were also annotated in some species, but no chaperones or storage proteins were annotated in any Lactobacillaceae strain analysed (Supplementary Table S6). Among annotated zinc-associated proteins, less than 6% are classified as uptake transporters for E. coli K12, B. subtilis 168, and the Lactobacillaceae strains (Fig. 1B and Supplementary Table S5). Five out of 13 of the Lactobacillaceae strains did not have any of the zinc uptake proteins from Table 1 annotated. We included MntH as a secondary zinc transporter given experimental evidence that it can transport zinc in addition to the primary function as a manganese transporter.³⁸ Most of the uptake proteins identified here as zinc-associated in Lactobacillaceae are MntH, and although MntH has been experimentally confirmed for manganese transport in some species of Lactobacillaceae, it has not been tested for any possible roles in zinc transport (Supplementary Table S6).^51–53 Several Mg²⁺ transporters that may also be involved in Zn²⁺ transport were annotated,^54–58 including CorA in Lactobacillus acidophilus NCFM and Ligilactobacillus salivarius UC118, MgtA in Lactobacillus crispatus ST1 and L. rhamnosus GG, and MgtE in L. salivarius UC118. The only strain annotated with some domains from the well-characterized high-affinity Zn²⁺ transporter ZnuABC was L. plantarum WCFS1 (Supplementary Table S6). Transporters associated with zinc efflux were found in six of the Lactobacillaceae strains (1-2 each). By comparison, E. coli K12 has four and B. subtilis 168 has two annotated zinc efflux proteins from Table 1 (Supplementary Table S6). Several strains of Lactobacillaceae had CadA efflux transporters annotated and L. salivarius UCC118 had ZntA (Supplementary Table S6). CzcD was also annotated in L. salivarius UCC118 and L. plantarum WCFS1. Collectively, this assessment of the current annotation of the complete proteomes (UniProtKB) for several well-studied strains with intestinal or probiotic relevance reveals that few or no zinc transporters were previously identified or predicted. Aside from MntH, the only other annotated metal transporter that has been experimentally verified in Lactobacillaceae is the CadA transporter for cadmium transport.⁵⁹ Therefore, none of the annotated transporters described earlier have been experimentally verified for zinc and are only predicted in UniProtKB. Although significant numbers of zinc-associated proteins with other functions were predicted, the total numbers of zinc proteins predicted fall short of the well-studied model organisms, E. coli K12 (gram negative) and B. subtilis 168 (gram positive) (Fig. 1B). Despite the lack of currently annotated zinc transporters, Lactobacillaceae require zinc for survival and have zinc proteomes implying that they should also have mechanisms for zinc transport and regulation, thereby warranting a deeper investigation to identify zinc transporters in these bacteria.

Table 1.

Zinc transporter query set

Type	Protein	Family	Accession ID	Length	Function (Reference)
Uptake	AdcA	ABC transporter	WP_000724057.1 ^a	501	High-affinity zinc uptake, substrate-binding protein domain (fusion protein comprised of a ZnuA-like portion and a ZinT-like portion), usually found in gram-positive bacteria (^63,96)
	AdcB	ABC transporter	WP_000950018.1	268	High-affinity zinc uptake, membrane permease domain, usually found in gram-positive bacteria (^63,96)
	AdcC	ABC transporter	WP_001269474.1	234	High-affinity zinc uptake, ATPase domain, usually found in gram-positive bacteria (⁶³)
	ZnuA	ABC transporter	WP_010971688 ^a	329	High-affinity zinc uptake, substrate-binding protein domain, usually found in gram-negative bacteria (formerly YcdH) (⁶⁰)
	ZnuB	ABC transporter	WP_003246340.1 ^a	280	High-affinity zinc uptake, membrane permease domain, usually found in gram-negative bacteria (formerly YceA) (⁶¹)
	ZnuC	ABC transporter	WP_003234730.1 ^a	231	High-affinity zinc uptake, ATPase domain, usually found in gram-negative bacteria (formerly YcdI) (⁶²)
	TroA	ABC transporter	WP_010881610.1 ^a	308	High-affinity zinc uptake, periplasmic metal-binding protein domain (⁶⁴)
	TroB	ABC transporter	WP_010881611.1 ^a	266	High-affinity zinc uptake, ATPase domain (⁶⁴)
	TroC	ABC transporter	WP_010881612.1 ^a	298	High-affinity zinc uptake, part of the heterodimeric cytoplasmic membrane permease TroCD (⁶⁴)
	TroD	ABC transporter	WP_014342310.1 ^a	367	High-affinity zinc uptake, part of the heterodimeric cytoplasmic membrane permease, TroCD (⁶⁴)
	ZinT	Bacterial solute-binding protein 9	WP_002882986	216	Periplasmic high-affinity zinc-binding protein, facilitates metal uptake by ZnuABC under zinc-limited conditions (formerly YodA) (^66,67)
	ZnuD	TonB-dependent receptor	WP_118820519.1 ^a	758	High-affinity zinc uptake, outer membrane protein that is a TonB-dependent receptor (⁶⁸)
	ZupT	ZIP	WP_001295627.1	257	Low-affinity zinc uptake, slight preference for zinc but broad metal specificity that also includes cadmium, cobalt, iron, manganese, and possibly copper (^70–72)
	ZosA	P-type ATPase	O31688	637	Zinc uptake under micromolar zinc levels, important for oxidative stress resistance, also referred to as P-type heavy metal-transporting ATPase (PfeT, ^61,73)
	MgtA	P-type ATPase	P0ABB8	898	Mg²⁺ transporter that may also transport zinc. Mg²⁺ transport is inhibited by Zn²⁺ (^55–57,76)
	MgtE	SLC41A transporter	Q5SMG8	450	Mg²⁺ transporter with diverse specificity and which many also confer Zn²⁺ uptake into prokaryotic cells (^55,56,58)
	CorA	CorA metal ion transporter	WP_010870546	317	Conductive magnesium channel with low selectivity that can also transport Cd²⁺, Co²⁺, Ni²⁺, and Zn²⁺ (⁵⁴)
	ZntB	CorA metal ion transporter	WP_000387373	327	Proton-coupled symporter, likely mediates zinc uptake but also proposed to act as a zinc exporter. Can also transport Cd²⁺, Co²⁺ and Ni²⁺. See also CorA (^54,74,78,79)
	PitA	Inorganic phosphate transporter	WP_000902780.1	499	Low-affinity inorganic phosphate transporter also involved in Zn²⁺ uptake and transport of arsenate (^74,77)
	ZrmA	TonB-dependent receptor	WP_004365419.1	708	Mediates uptake of pseudopaline-Zn²⁺ complex under zinc-limited conditions, outer membrane protein that is a TonB-dependent receptor, gene name is cntO (^80,81)
	YbtX	Major Facilitator Superfamily	WP_005168691.1	426	Mediates uptake of Zn²⁺ via small molecule(s), modified yersiniabactin or yersiniabactin and another compound (⁸²)
	MntH	NRAMP	WP_000186369.1	412	Mn²⁺ transporter involved in secondary zinc import (³⁸)
Efflux	ZntA	P-type ATPase	P37617	732	Zn²⁺-exporting ATPase. Confers resistance to Zn²⁺, Cd²⁺, Pb²⁺, and Co²⁺ and binds to Hg²⁺ (^83,84)
	CadA	P-type ATPase	O32219	702	Cd²⁺, Zn²⁺, and Co²⁺-transporting ATPase that couples the hydrolysis of ATP with export of Cd²⁺, Zn²⁺, and Co²⁺ (⁸⁵)
	ZitB	CDF	WP_000951292.1	313	Zn²⁺-selective efflux transporter, does not confer resistance to Co²⁺ or Cd²⁺ (⁸⁷)
	YiiP	CDF	P69380	300	YiiP (FieF) is a divalent metal cation transporter that exports Zn²⁺, Cd²⁺, and possibly Fe²⁺ (^88–90)
	CzcD	CDF	P13512	316	Zn²⁺ efflux transporter that can also bind Co²⁺, Cu²⁺, and Ni²⁺ (^91,92)
	CzcA	RND	WP_011229347.1 ^a	1063	Inner membrane-spanning component of the CzcABC efflux system. Transports Zn²⁺, Cd²⁺, and Co²⁺ (^94,95)
	CzcB	RND	WP_004635340.1 ^a	520	Periplasmic adaptor protein component of the CzcABC efflux system. Transports Zn²⁺, Cd²⁺, and Co²⁺ (^94,95)
	CzcC	RND	WP_011514819.1 ^a	418	Outer membrane-spanning component of the CzcABC efflux system. Transports Zn²⁺, Cd²⁺, and Co²⁺ (^94,95)
	ZntB	CorA metal ion transporter	WP_000387373	327	Proton-coupled symporter, likely mediates zinc uptake but also proposed to act as a zinc exporter. Can also transport Cd²⁺, Co²⁺, and Ni²⁺. See also CorA (^54,74,78,79)

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^aModel protein or representative protein of the BlastRule protein family found on NCBI Protein Family Models (see Supplementary methods).

Prediction of zinc transporters in Lactobacillaceae using BLASTP

To carry out a sequence-based search for zinc transporter homologs in Lactobacillaceae species, we compiled a set of bacterial zinc transport proteins from NCBI and UniProtKB. Then, we used them as queries to perform BLASTP searches against the NCBI non-redundant database for homologs first in representative species and then across all species of seven genera of Lactobacillaceae with intestinal relevance. Using the results of the latter BLASTP search, we predicted and assembled core and genus-specific zinc transportomes. Finally, and because most BLASTP hits for zinc ABC transporters were a mix of one or more domains from different model transporters, we evaluated the location of each hit in the genomes of several representative Lactobacillaceae species and used this information to assemble predicted zinc transporter operons and compared these operon structures between genera and with model organisms.

Building a bacterial zinc transporter query set

To search for putative zinc transporters in the Lactobacillaceae family (Scheme 1), we identified and categorized experimentally studied zinc transporters from other bacterial species (“Supplementary methods,” Table 1; Fig. 2).^{1,9,16,35–37}

Fig. 2 — Overview of major zinc uptake and efflux transporters and types of transporters found in gram-positive and gram-negative bacteria. Bacteria use high-affinity ABC transporters for zinc uptake (AdcABC in gram-positive and ZnuABC in gram-negative although this division is not strictly adhered to). TroABCD is a similar transporter found in several Treponema species. ZinT is a proposed periplasmic zinc binding protein that facilitates Zn²⁺ uptake. ZupT is a low-affinity transporter. P-type ATPases such as ZosA and MgtA are also involved in zinc uptake. ZnuD is an outer membrane TonB-dependent high-affinity zinc uptake protein. Bacteria primarily use P-type ATPases (ZntA, CadA), CDFs (ZitB, YiiP, CzcD), and membrane-spanning RND systems (CzcABC) for zinc efflux. P-type ATPase efflux transporters are significantly more represented than P-type ATPase uptake transporters (shaded gray) in bacterial genomes. Additional transporters that can or may contribute to zinc homeostasis in bacteria are detailed in Table 1.

High-affinity zinc uptake transporters

Proteins involved in primary zinc import include members of the ABC superfamily and zinc–iron permease (ZIP) family members. High-affinity zinc uptake ABC transporters are widespread in bacteria and include ZnuABC (usually in gram-negative bacteria), AdcABC (usually in gram-positive bacteria), and TroABCD.^60–64 AdcA is similar to ZnuA, except it is fused with a ZinT-like portion. The selectivity of AdcA for zinc in Streptococcus pneumoniae has been established in vivo.⁶⁵ ZinT is a specialized high-affinity periplasmic zinc-binding protein that can be used to facilitate zinc uptake by the ZnuABC system and is important for growth under zinc-limited conditions.^66,67 Gram-negative bacteria also use the outer-membrane TonB-dependent zinc importer, ZnuD.^68,69 Although gram-positive Lactobacillaceae do not have outer membranes, we still included ZnuD and other outer membrane or gram-negative bacteria-specific transporter sequences to search for similar zinc binding sites.

Other zinc uptake transporters

ZupT is a low-affinity zinc transporter from the ZIP family of transporters that can also transport other divalent metal ions including iron, manganese, and cadmium.^70–72 In addition to the earlier-mentioned transporters, there are several other zinc uptake transporters found in different bacteria. ZosA is a P-type ATPase thought to be involved in Zn²⁺ uptake under oxidative stress conditions in B. subtilis.^61,73 Transporters with diverse metal specificity that may be involved in Zn²⁺ uptake include the CorA metal ion transporter,^54,74 the P-type ATPase transporter MgtA,^{55–57,75,76} MgtE of the SLC41A transporter family,^55,56,58 and the inorganic phosphate transporter PitA.^74,77 ZntB, which is part of the CorA metal ion transporter family, is associated with Zn²⁺ uptake but has also been proposed to export zinc.^54,74,78,79 Zinc can also be obtained using secreted small molecules in some bacteria. Under zinc-limited conditions Pseudomonas aeruginosa can employ the TonB-dependent receptor ZrmA to obtain Zn²⁺ bound to pseudolapine.^80,81 Similarly, Yersinia pestis harbors YbtX, a member of the Major Facilitator Superfamily, which is involved in zinc uptake likely using modified yersiniabactin or yersiniabactin and a second compound.⁸² Secondary zinc import may also occur through MntH, a natural resistance-associated macrophage protein (NRAMP) superfamily member primarily involved in Mn²⁺ uptake.⁵⁵

Zinc efflux transporters

Zinc efflux from bacterial cells is primarily facilitated by P-type ATPases, members of the CDF family, and resistance–nodulation–cell division (RND) systems. ZntA and CadA are P-type ATPase transporters that are involved in cellular redistribution and detoxification of Zn²⁺ and other metals like Cd²⁺ and Pb²⁺.^83–85 P-type ATPase efflux transporters are significantly more represented than uptake transporters in bacterial genomes.⁸⁶ Furthermore, the activities and mechanisms of P-type ATPases as metal exporters have been investigated more extensively than P-type ATPase metal importers. CDF family transporters for Zn²⁺ efflux include ZitB,⁸⁷ YiiP,^88–90 and CzcD.^91,92 Aside from YiiP, metal selectivity in many CDF transporters has not been very well defined.⁹³ RND systems like CzcABC are found in gram-negative bacteria and comprise a trimeric A component that spans the inner membrane and reaches into the periplasm, a trimeric C component that spans the outer membrane and also reaches into the periplasm, and periplasmic B adaptor proteins, six of which link the two trimers.^1,94,95 As described earlier, the Zn²⁺ uptake transporter ZntB has also been proposed to be involved in Zn²⁺ efflux.^74,78,79

There are many similar sequences for most of the transporters described earlier, so model proteins retrieved from NCBI Protein Family Models (PFMs) or high scoring (4/5 or 5/5) UniProtKB entries were relied upon, as described in Supplementary methods. Paralogs (e.g. AdcA and AdcAII or ZnuD and ZnuD2)^69,96 are also included in the PFMs defined by BlastRules. The model proteins used represent each of the PFMs.

BLASTP search for zinc transporters in representative Lactobacillaceae species

For each zinc transporter chosen to be part of the query set, a comprehensive BLASTP search was carried out for the representative species of seven Lactobacillaceae genera chosen for this work (Scheme 1, Supplementary methods). BLASTP hits for several zinc uptake (Fig. 3) and efflux (Fig. 4) transporters were found in all Lactobacillaceae species investigated here. For the three zinc uptake ABC transporters (AdcABC, ZnuABC, and TroABCD), we searched for each domain separately in Lactobacillaceae. To compare the similarity of each type of domain between different ABC transporters and facilitate analysis of the BLASTP search results, we calculated similarity matrices (Supplementary Fig. S2), and performed sequence alignments between substrate-binding domains (A), permease domains (B in Adc and Znu, CD in Tro), and ATPase domains (C in Adc and Znu, B in Tro). BLASTP hits for the substrate-binding (AdcA) and ATPase (AdcC) domains of the high-affinity zinc uptake protein AdcABC were found in all investigated species. None of the search hits matched more than 60% query coverage of the AdcA sequence, however, and lacked the ZinT portion of the reported AdcA sequence. This result is consistent with the lack of hits for ZinT. Many Lactobacillus species had matches for the ZnuB permease domain instead of AdcB and most Limosilactobacillus species did not have matches for any of the searched permease domains. All investigated species had sequences similar to the ATPase domains ZnuC and TroB, and ZnuB was also common in most genera except Limosilactobacillus. The substrate-binding domain ZnuA was found in few species. The substrate-binding domain TroA was found in most investigated species except those in the Lactobacillus and Limosilatobacillus genera. The heterodimeric permease TroCD was found in all investigated species in the Latilactobacillus, Lacticaseibacillus, and Lactiplantibacillus genera. Collectively, these BLASTP search results for the different components of several high-affinity zinc ABC transporters reveal that most species of nearly all genera of Lactobacillaceae investigated here likely have complete zinc ABC transporters. Only the Limosilactobacillus genus yielded few BLASTP hits for a permease domain.

Fig. 3 — Occurrence of zinc uptake protein sequences in representative intestinal *Lactobacillaceae* species. The heat map shows the BLASTP hits found for each transporter in the corresponding species and is mapped to colors using the minimum (blue) and maximum (red) numbers of BLASTP hits for each species (row) independently. White boxes indicate transporters/species with no BLASTP hits. The schematic species tree on the left shows the taxonomic relationship between these species. Total BLASTP hit values shown at the bottom represent the total numbers for all of the representative species listed at the right on this figure.

Aside from zinc ABC transporters, several other zinc uptake proteins were searched for matches to Lactobacillaceae proteomes using BLASTP (Table 1; Fig. 3). Among these, only ZosA and MgtA may be predicted to be widespread in Lactobacillaceae given that that there were BLASTP hits for these in all of the species. Only a few hits were found for ZupT, MgtE, CorA, and PitA and no hits were found for ZnuD, ZntB, ZrmA, and YbtX.

The BLASTP search also uncovered various zinc efflux transporters (Fig. 4). The P-type ATPases CadA and ZntA were found in all investigated species. The CDFs ZitB and CzcD were found in all investigated species except Latilactobacillus and Ligilactobacillus species. YiiP was mostly detected in the Lactobacillus genus. There were no hits for the metal ion transporter ZntB, which has been implicated in zinc export in addition to uptake.^78,79 Few species had any sequences similar to the inner membrane CzcA component of the gram-negative CzcABC efflux system and none had matches for any of the other components. These CzcA hits were only found in L. plantarum and Limosilactobacillus oris. SmartBLAST and domain searches revealed that these hits belong to the AcrB family. AcrB is the inner membrane component of the AcrAB–TolC drug efflux system in E. coli and functions as a proton–motive force-driven transporter with wide substrate specificity. Previous studies found that the AcrD homolog of this transporter can also function as zinc exporter.^97,98 A Basic Local Alignment Search Tool (BLAST) search for AcrA, the periplasmic adaptor subunit of this drug efflux system, also yields hits in L. plantarum and L. oris, but there are no hits from a BLAST search for TolC (the outer membrane channel). These findings warrant further investigation into predicted RND-type efflux systems in Lactobacillaceae that may be related to the RND exporters found in gram-negative bacteria.

Next, we aimed to directly compare the BLASTP homology search results with the currently annotated zinc transporters found in UniProtKB. Here we compared the UniProtKB annotations from the 13 Lactobacillaceae strains and the two model organisms with BLASTP search results by both strain and, more broadly, by species (Fig. 5). In general, the model organisms E. coli K12 and B. subtilis 168 were well annotated, with significant overlap in the UniProtKB annotation and BLASTP search results, although there were still some BLASTP hits that were not identified in our UniProtKB annotation search. Some of these may be present in transporter subfamilies with high probabilities for substrates other than zinc. For example, the CzcA hit for B. subtilis 168 (and L. plantarum) belongs to the multidrug efflux pump AcrB family as discussed earlier, whereas the CzcA hit for E. coli belongs to the copper/silver efflux pump CusA family. By comparison, there was very little or no overlap for the Lactobacillaceae strains due to the significant lack of UniProtKB annotations, especially for predicted zinc-specific uptake transporters. The most widespread overlap across species occurred for MntH, which is primarily attributed to Mn²⁺ transport and has not yet been tested for any role in secondary Zn²⁺ transport in Lactobacillaceae.^54–56,58

Fig. 5 — Comparison of zinc transport proteins found via UniProtKB annotation and BLASTP search for representative intestinal *Lactobacillaceae* species. Black indicates transporters only found by UniProtKB annotation. Transporters found by both UniProtKB annotation and BLASTP are colored red if BLASTP hits are from the indicated strain, and gray if BLASTP hits are from the indicated species. For transporters found only by BLASTP search, blue indicates strain-specific hits and green indicates species-specific hits.

Assembling predicted zinc transportomes by genus in Lactobacillaceae

Next, we expanded our BLASTP search to include all species belonging to the seven investigated Lactobacillaceae genera. This expansion allowed us to assemble the BLASTP search results to yield a core zinc transportome encompassing the predicted zinc transporters that were present among all genera investigated (Scheme 1; Fig. 6; Supplementary Tables S7 and S8). Similar to the species-specific search earlier, here we found that homologs of components of the AdcABC transporter were more frequently present in Lactobacillaceae than ZnuABC components and components of the TroABCD system. Specifically, AdcA and AdcC were found in all representative species discussed earlier (Fig. 3) and here when the search is expanded there are still BLASTP hits for AdcA and AdcC in many, albeit not all species of each genus (Fig. 6A; Supplementary Table S7). As observed for the search in representative species, the permease (AdcB) domain was found in many species of all genera except Lactobacillus and Limosilactobacillus (Fig. 6A). All genera also had sequences similar to the ATPase ZnuC component, and ZnuB was also common in most genera except Limosilactobacillus. The substrate-binding domain ZnuA was found in <30% of species of each genus except Lactobacillus and Levilactobacillus, which both yielded no BLASTP hits. An analysis of the ZnuA hits revealed significant overlap with the AdcA results. In addition to ZnuB and ZnuC, other ABC transporter components (TroA, TroB) were also found in all genera. These BLASTP search results often overlapped for the components with similar sequences (e.g. AdcB/ZnuB and AdcC/ZnuC, Supplementary Fig. S2). The ATPase domain TroB, like ZnuC and AdcC, was found in most species. The substrate-binding domain TroA was found in at least some species from each genus, but with many hits in Lacticaseibacillus, Lactiplantibacillus, and Latilactobacillus genera. Similarly, TroC and TroD, which make up the heterodimeric permease domain TroCD in TroABCD, were found in all species in the Latilactobacillus genus and many species in the Lacticaseibacillus and Lactiplantibacillus genera, but in few or no species from the other four genera (Fig. 6A).

Fig. 6 — Percentage of zinc uptake (A) and efflux (B) protein BLASTP hits relative to all species searched in each intestinal *Lactobacillaceae* genus. Transporters that did not yield any hits are not shown (uptake: ZnuD, ZntB, ZrmA, and YbtX; efflux: CzcB, CzcC, ZntB).

Homologs for the low-affinity ZupT zinc uptake protein were rare in Lactobacillaceae, but homologs for some other low-affinity or broad-spectrum zinc uptake proteins were found across many Lactobacillaceae (Fig. 6A). Specifically, ZosA and MgtA can be predicted to be widespread in Lactobacillaceae with BLASTP hits found in most species of each genus searched (Figs 3 and 6A). These transporters are homologs with 23% identity (Supplementary Fig. S2). ZosA was previously shown to be important in B. subtilis under oxidative stress conditions where Zn²⁺ concentrations are >1 µM and the high-affinity ZnuABC transporter is repressed.^61,73 Notably, a mutant of Lactococcus lactis lacking regulators for high- and low-affinity P-type ATPase zinc uptake systems is sensitive to oxidative stress and has low intracellular zinc levels.⁹⁹ L. lactis is from a different taxonomic family, Streptococcaeae, but shares the same order, Lactobacillales, with Lactobacillaceae.^100–102 A BLASTP search yields hits for ZosA in L. lactis suggesting that perhaps one of the P-type ATPase uptake systems in L. lactis is ZosA. Whether similar connections between zinc and oxidative stress can be found in Lactobacillaceae and linked to ZosA or other zinc transporter homologs is an open question. MgtA is a magnesium transporter that may also transport Zn²⁺.^55–57 A study in L. lactis found that MgtA is downregulated under low pH stress, but metal ion transport was not studied and this transporter has not yet been investigated in Lactobacillaceae.¹⁰³

There were fewer BLASTP hits for several other transporters that may have broad metal specificity or for which Zn²⁺ transport may be just a secondary function (Fig. 6A). Homologs for MgtE were found in only one or a few species of Lacticaseibacillus and Lactobacillus, and in many species of Ligilactobacillus. CorA homologs were found in all genera but only for the Lacticaseibacillus genus was it detected in more than >50% of species. MgtE and CorA are both primarily involved in Mg²⁺ transport in other bacteria, but have broad metal specificity that can include Zn²⁺.^54–56,58 These transporters have not yet been studied in Lactobacillaceae. There were a few BLASTP hits for PitA across the Lactiplantibacillus, Lactobacillus, and Limosilactobacillus genera and there were no matches for ZntB, ZrmA, or YbtX. Homologs for MntH, however, were found in all genera and were widespread among species of each genus except Lactobacillus (Figs 3 and 6A). Several MntH transporters have been investigated in Lactiplantibacillus plantarum WCFS1 and were found to be upregulated in response to manganese starvation although mutants of these did not exhibit any growth defects or decreases in intracellular Mn²⁺ levels.⁵¹ Some L. brevis isolates also code for an MntH transporter that is required for survival at low pH.⁵³ Metal selectivity and the effects of other metals such as zinc on these transporters have not been investigated.

The results for the predicted zinc efflux transporters across all species of each genus were, as for the uptake transporters, generally similar to those found for the representative species (Figs 4 and 6B). Homologs for the P-type ATPases CadA and ZntA were found in all genera and most species searched (Fig. 6B; Supplementary Table S8). CadA and ZntA have 36% identical residues and are both involved in Zn²⁺ efflux in other bacteria (Supplementary Fig. S2).^{83–85,104,105} Because of the sequence similarity, the BLASTP search results for CadA and ZntA overlapped significantly (>∼80%). CadA has been identified and studied in the context of Cd²⁺ toxicity in some strains of L. plantarum, but zinc was not studied.⁵⁹ In L. lactis, a P-type ATPase protein that was most similar in sequence to ZntA was studied but only in the context of zinc uptake (as discussed earlier), and a link was found between low intracellular zinc and increased sensitivity to oxidative stress.⁹⁹ P-type ATPases are known to play a role in copper export in L. lactis and likely in L. delbrueckii subsp. bulgaricus under acid stress conditions although transport of other metals has not been excluded.^106,107 A Mn²⁺/Cd²⁺ uptake P-type ATPase has also been characterized in L. plantarum.¹⁰⁸ Homologs for zinc efflux CDFs were also found in Lactobacillaceae, but not in all genera (Fig. 6B). BLASTP hits for ZitB and CzcD were found in all genera except Latilactobacillus and have 39% sequence similarity (Supplementary Fig. S2). ZitB and CzcD are both involved in conferring zinc resistance in bacteria but their specific roles in Lactobacillaceae have not been investigated.^87,91,92 YiiP homologs were mostly detected in Lactobacillus (33% of species) with just 5–6% of species in the Ligilactobacillus and Limosilactobacillus genera yielding BLASTP hits. Homologs for the inner membrane portion of the RND efflux transporter, CzcA, were found in a few species of Lactiplantibacillus and Limosilactobacillus.

The earlier results allow us to predict a core zinc transportome among these seven Lactobacillaceae genera comprised only of zinc transporters present in 50–100% of species for each genus. Here, the predicted core uptake transporters include zinc uptake ABC transporters (comprised mainly of BLASTP hits for the substrate-binding domain AdcA and the ATPase domains AdcC, ZnuC, and TroB) and the P-type ATPases ZosA and MgtA (Fig. 6A). We note that most genera also had hits for the permease domain AdcB, with the exception of Lactobacillus that had more hits for ZnuB and Limosilactobacillus that had few hits for any permease domain in the query set. The predicted core efflux transporters are the P-type ATPases ZntA and CadA (Fig. 6B).

Similarly, we can also identify some predicted transporters that are genus-specific. MgtE, which is primarily involved in magnesium transport, is predicted in most species of the Ligilactobacillus genus. CorA hits were common in the Lacticaseibacillus genus and MntH hits were found in most or all species of each genus except Lactobacillus. For predicted zinc efflux transporters, homologs for the CDFs ZitB and CzcD were common among Lacticaseibacillus, Lactiplantibacillus, Levilactobacillus, Limosilactobacillus, and Lactobacillus genera.

Collectively, whether any of these predicted zinc transporters play primary or secondary roles in zinc import or efflux and any relationships with oxidative stress or pH stress conditions in Lactobacillaceae is worthy of future experimental studies.

Operon analysis of predicted zinc uptake ABC transporters

We found that the most common BLASTP hits for zinc uptake ABC transporters were a mix of components from different transporters (i.e. AdcABC vs. ZnuABC), but close examination of the results revealed missing components in some species (e.g. a permease domain for many species in the Limosilactobacillus genus, Figs 3 and 6A). Therefore, to predict the likelihood of the different search result components to assemble into a complete ABC transporter, we examined their sequence locations using published genomes of several strains across the seven genera. Using this information, we assembled predicted zinc ABC transporter operons and compared these operon structures between genera and with model organisms. Due to sequence similarity between query transporters (Supplementary Fig. S2), there is significant overlap between the search query substrate-binding domains (AdcA, ZnuA, and TroA), permease domains (AdcB and ZnuB), and ATPase domains (AdcC and ZnuC, and TroB). For this operon analysis, we investigated four well-studied species from the Lactobacillus genus and found that three of these had similar ABC transporter operon structures. Specifically, L. acidophilus NCFM, L. crispatus ST1, and L. gasseri ATCC 33323 all yielded an AdcA-like substrate-binding domain (60% query cover, with no ZinT-like portion, Fig. 7; Supplementary Table S9), an ATPase domain as the search result for each of the three ATPase queries (AdcC, ZnuC, and TroB), and a permease domain as a search result only for ZnuB. Lactobacillus delbrueckii ATCC 11482, on the other hand, yielded similar results for the ATPase and permease domains, however there was no substrate-binding domain found using AdcA, ZnuA, or TroA as search queries. Examination of the genes around the permease and ATPase domain homologs in this strain revealed no sequences similar to known ABC transporter substrate-binding domains, but a gene containing the sequence for a zinc ribbon domain was found. It is possible that this gene could act as the substrate-binding domain for an ABC transporter in L. delbrueckii.

Fig. 7 — Predicted operons for zinc uptake ABC transporters in select strains within several genera of *Lactobacillaceae*. Genes for each of the domains (A: substrate-binding domain; ZnuC/AdcC/TroB: ATPase domain; and ZnuB/AdcB/TroCD: permease domain) are based on the search results for ZnuABC, AdcABC, and TroABCD as indicated by the depiction of AdcA-like or AdcC/ZnuC/TroB-like, etc. on each gene. In some cases, the domain was not found in any search and only discovered based on its proximity to the other search results (e.g. the “permease” domains in each *Limosilactobacillus* strain and the Zn ribbon domain-containing protein in *L. delbrueckii* ATCC 11842). Arrows indicate the direction of transcription. Operons were assembled according to searches and analyses of the following genomes: *L. acidophilus* NCFM, NC_006814.3; *L. crispatus* ST1, NC_014106.1; *L. delbrueckii* ATCC 11842, NC_008054.1; *L. gasseri* ATCC 33323, NC_008530.1; *L. reuteri* DSM 20016/JCM 1112, NC_009513.1; *L. fermentum* IFO 3956, NC_010610.1; *L. vaginalis* ATCC 49540, NZ_CP104399.1; *L. paracasei* ATCC 334, NC_008526.1; *L. rhamnosus* GG, NC_013198.1; *L. salivarius* UCC118, NC_007929.1; *L. plantarum* WCFS1, NC_004567.2; *L. sakei* 23 K, NC_007576.1; *L. brevis* ATCC 367, NC_008497.1; *E. coli* K12, NC_000913.3; and *B. subtilis* 168, NC_000964.3. A summary of the search results including locus tags and gene ID numbers for each domain are reported in Supplementary Table S9.

The three species investigated from the Limosilactobacillus domain had identical ABC transporter operon structures. As for most of the Lactobacillus genus, there is an AdcA-like substrate-binding domain and an ATPase domain like all of the queried ATPase domains. Conversely, there was no result similar to any of the queried permease domains. Examination of the genes near the substrate-binding and ATPase domains revealed, however, that there was a sequence predicted to be a permease domain. Each of these permease domains found in the Limosilactobacillus strains have ∼75–80% sequence similarity to each other, but only ∼20% sequence similarity to AdcB, ZnuB, TroC, and TroD (Supplementary Fig. S3).

The two strains in the Lacticaseibacillus genus also have similar ABC transporter operon structures. Here, the search results for each domain were the same for each of the queried transporters (AdcABC, ZnuABC, and TroABCD). The strains from each of the remaining four genera, Ligilactobacillus, Lactiplantibacillus, Latilactobacillus, and Levilactobacillus, all had complete operons with domains that were the search results of one or more of the query transporters. Each genus had a substrate-binding domain that was similar to AdcA (lacking the ZinT portion) and TroA, except Levilactobacillus, which had a substrate-binding domain that was only similar to TroA. The permease domain in each genus was similar to both AdcB and ZnuB, and the Lactiplantibacillus strain had a permease domain that was also similar to TroCD. Each of the four strains had ATPase domains similar to one or more of those searched.

There is significant variation in the relative order of genes for the predicted ABC transporter domains in each genus or strain. In most Lactobacillus, Limosilactobacillus, Ligilactobacillus, and Levilactobacillus the substrate binding domain is found furthest upstream and followed by the ATPase and then permease domains, similar to the gram-positive model organism B. subtilis 168. On the other hand, Lacticaseibacillus, Lactiplantibacillus, and Latilactobacillus all have operon structures where the ATPase domain appears upstream of the permease domain and then the substrate-binding domain. Although these putative zinc ABC transporter operon structures are defined only for select strains of Lactobacillaceae, these results highlight a potentially interesting and possibly genus-specific diversity in predicted zinc uptake ABC transporters across the Lactobacillaceae family, which calls for future experimental studies to determine specific roles and requirements of these transporters for metal uptake. Although no zinc ABC transporters have been studied in Lactobacillaceae, some studies have investigated an operon containing a putative high-affinity zinc uptake transporter and the associated promoter and repressor in L. lactis. The regulator, designated ZitR, and which is similar to AdcR, is derepressed under starvation conditions (<nM) and repressed at micromolar concentrations.¹⁰² An additional lower-affinity uptake transporter was proposed but not identified. A search for the regulators AdcR and Zur revealed that Zur is present in all seven Lactobacillaceae genera investigated here (data not shown). AdcR was found in some Lactobacillaceae, but there were far fewer BLASTP hits compared to Zur.

Conclusion

In this perspective, we provide a comprehensive bioinformatic analysis of a series of zinc transporter homologs found in several intestinally relevant genera of Lactobacillaceae. Zinc is essential in Lactobacillaceae, yet no uptake or efflux transporters confirmed to play a role in zinc transport in this family of bacteria have been studied. The lack of such work limits understanding of how these bacteria respond to changes in zinc availability and why they are frequently correlated with changes in dietary zinc. We first demonstrated that the current sequence annotation of zinc transporters in Lactobacillaceae proteomes found on the UniProt database is incomplete. Even among those that are annotated, none have been experimentally tested or verified for roles in zinc transport. Next, by assembling a zinc transporter query set with the protein sequences of experimentally characterized zinc uptake and efflux transporters from other bacteria and searching across seven intestinally relevant genera of Lactobacillaceae, we identified a core set of common zinc transporters and several others found only in select genera. Homologs for high-affinity zinc ABC uptake transporters and lower-affinity P-type ATPase transporters possibly involved in zinc uptake were present across all genera investigated here. ABC transporter operon analysis for several representative strains revealed significant diversity in these transporters between Lactobacillaceae genera and identified a potentially novel substrate binding component in L. delbrueckii. These predicted ABC and P-type ATPase transporters might be sufficient for Lactobacillaceae to accumulate the zinc needed for survival and possibly for competition in a multi-species environment. Examining these transporter homologs experimentally would be an excellent starting point to test this hypothesis in Lactobacillaceae species. Among other transporters potentially involved in zinc uptake, only MntH was found in many species of most genera (except Lactobacillus). Homologs for P-type ATPase efflux transporters, ZntA and CadA, were found in all Lactobacillaceae genera, while those for CDF efflux transporters, ZitB and CzcD, were found in all genera except Latilactobacillus. Based on studies in other bacteria, these predicted efflux transporters may confer resistance to toxic zinc levels and could even play roles in acid stress for Lactobacillaceae. Experimental studies on these zinc efflux homologs in different Lactobacillaceae species are also needed. Beyond the transporters predicted here based on sequence homology, we note that there are many uncharacterized proteins among Lactobacillaceae. By combining bioinformatic and experimental approaches to investigate these proteins, novel zinc-associated transporters may be revealed in Lactobacillaceae.

Overall, this perspective sets a foundation for and highlights the numerous opportunities for studying predicted zinc transporters in Lactobacillaceae. This foundation is a crucial step in understanding and predicting the impacts of zinc on the composition of the gut microbiota and to understanding the zinc biology of Lactobacillaceae. Given that these bacteria are intricately linked with human health, such work could lead to novel therapeutics for disease or infection.

Supplementary Material

mfad044_Supplemental_Files

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Acknowledgements

We would like to acknowledge support from the National Institutes of Health National Institute of General Medical Sciences, the Welch Foundation, and the University of Houston. The authors would like to thank G. C. Jensen for valuable discussions and comments on this manuscript.

Contributor Information

Uyen Huynh, Department of Chemistry, University of Houston, Houston, TX 77204, USA.

Hazel N Nguyen, Department of Chemistry, University of Houston, Houston, TX 77204, USA.

Brittany K Trinh, Department of Chemistry, University of Houston, Houston, TX 77204, USA.

Joanna Elhaj, Department of Chemistry, University of Houston, Houston, TX 77204, USA.

Melissa L Zastrow, Department of Chemistry, University of Houston, Houston, TX 77204, USA.

Author contributions

U.H.: Conceptualization, Methodology, Data curation, Formal analysis, Investigation, Validation, Visualization, Writing Original draft preparation, Writing Review and Editing. H.N.N.: Data curation, Formal analysis, Investigation, Writing Review and Editing. B.K.T.: Methodology, Data curation, Formal analysis, Writing Review and Editing. J.E.: Data curation, Formal analysis. M.L.Z.: Conceptualization, Methodology, Formal analysis, Investigation, Validation, Visualization, Writing Original draft preparation, Writing Review and Editing, Funding Acquisition.

Funding

This work was supported by the National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS) grant R35 GM138223 (to M.L.Z.), the Welch Foundation grant E-1972 (to M.L.Z.), and the University of Houston.

Conflicts of interest

There are no conflicts to declare.

Data Availability

The data underlying this article are available in the paper and in the online supplementary material.

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PERMALINK

A bioinformatic analysis of zinc transporters in intestinal Lactobacillaceae

Uyen Huynh

Hazel N Nguyen

Brittany K Trinh

Joanna Elhaj

Melissa L Zastrow

Abstract

Graphical Abstract

Graphical Abstract.

Introduction

Scheme 1.

Analysis of Lactobacillaceae metalloproteome annotations from UniProtKB

Fig. 1.

Table 1.

Prediction of zinc transporters in Lactobacillaceae using BLASTP

Building a bacterial zinc transporter query set

Fig. 2.

High-affinity zinc uptake transporters

Other zinc uptake transporters

Zinc efflux transporters

BLASTP search for zinc transporters in representative Lactobacillaceae species

Fig. 3.

Fig. 4.

Fig. 5.

Assembling predicted zinc transportomes by genus in Lactobacillaceae

Fig. 6.

Operon analysis of predicted zinc uptake ABC transporters

Fig. 7.

Conclusion

Supplementary Material

Acknowledgements

Contributor Information

Author contributions

Funding

Conflicts of interest

Data Availability

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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