Variovorax periplasmic D-gluconate production, intracellular iron trafficking, metalloregulatory repression, polyphosphate turnover, and heavy-metal cation efflux and signaling

A functional grouping of six metabolic, polyphosphate, and metal-homeostasis subsystems across the cell envelope and cytoplasm of Variovorax paradoxus: (1) periplasmic PQQ-dependent glucose dehydrogenase (Gcd) oxidation of D-glucose to D-glucono-1,5-lactone coupled to membrane ubiquinone reduction in the D-gluconate pathway; (2) cytosolic YggX-family Fe(2+)-trafficking protein (FetP) binding of ferrous iron for intracellular iron transactions and Fe-S cluster assembly/repair; (3) Fe(2+)- and Zn(2+)-responsive transcriptional repression of iron- and zinc-uptake operons under metal sufficiency by the Fur-family metalloregulators Fur1 and Zur; (4) cytoplasmic inorganic polyphosphate (polyP) polymerization by polyphosphate kinase 1 (Ppk) and hydrolytic depolymerization to orthophosphate by exopolyphosphatase (Ppx); (5) transmembrane export of heavy-metal cations by the tripartite CzcCBA HME-RND trans-envelope efflux complex (CzcA3 inner-membrane RND antiporter, CzcB periplasmic membrane-fusion adaptor, and CzcC outer-membrane factor channel), the inner-membrane CzcD cation diffusion facilitator (CDF) antiporter, and the inner-membrane P1B-type Zn(2+)/Cd(2+) and Cu(+) efflux ATPases CadA2 and CopA2; and (6) periplasmic heavy-metal modulation by CzcI and His-Asp phosphorelay transcriptional regulation of heavy-metal efflux by the CusS-CzcR two-component signaling system.

MODULE:variovorax_metallophore_metal_homeostasisDRAFTBiological Processmodules/variovorax_metallophore_metal_homeostasis.yaml
intracellular iron ion homeostasisGO:0006879 monoatomic cation transmembrane transportGO:0098655
GO:0006879
intracellular iron ion homeostasis
GO:0006879 provides the biological-process context for cytosolic ferrous iron trafficking and intracellular iron homeostasis.
GO:0098655
monoatomic cation transmembrane transport
GO:0098655 provides the biological-process context for HME-RND- and CDF-mediated transmembrane export of monoatomic metal cations.
PMID:21183664
Complete genome sequence of the metabolically versatile plant growth-promoting endophyte Variovorax paradoxus S110.
Documents the metabolic versatility of Variovorax paradoxus S110 across heterotrophic, autotrophic, and plant-associated lifestyles.
Variovorax paradoxus is a microorganism of special interest due to its diverse metabolic capabilities, including the biodegradation of both biogenic compounds and anthropogenic contaminants.
PMID:10559151
CzcD is a heavy metal ion transporter involved in regulation of heavy metal resistance in Ralstonia sp. strain CH34.
Establishes the complementary roles of the tripartite CzcCB2A RND trans-envelope cation efflux complex and the inner-membrane CzcD CDF transporter in bacterial Co(2+)/Zn(2+)/Cd(2+) export.
The Czc system of Ralstonia sp. strain CH34 mediates resistance to cobalt, zinc, and cadmium through ion efflux catalyzed by the CzcCB(2)A cation-proton antiporter.
PMID:12829273
Efflux-mediated heavy metal resistance in prokaryotes.
Defines the three-component architecture of HME-RND heavy-metal efflux systems (inner-membrane RND pump CzcA, periplasmic membrane-fusion protein CzcB, and outer-membrane factor CzcC) alongside CDF-family inner-membrane antiporters (CzcD).
The mechanisms of action, physiological functions, and distribution of metal-exporting proteins are outlined, namely: CBA efflux pumps driven by proteins of the resistance-nodulation-cell division superfamily, P-type ATPases, cation diffusion facilitator and chromate proteins, NreB- and CnrT-like resistance factors.
PMID:23687963
Accumulation of inorganic polyphosphate enables stress endurance and catalytic vigour in Pseudomonas putida KT2440.
Establishes that bacterial inorganic polyphosphate turnover is governed by the opposing activities of polyphosphate kinase (Ppk) and exopolyphosphatase (Ppx).
In addition to Ppk, there is another polyP-modifying enzyme: the so-called exopolyphosphatase (Ppx), that is in charge of polyP hydrolysis to Pi (Figure 1A).
file:VARPD/gcd/gcd-ai-review.yaml
Variovorax paradoxus gcd gene review
A0A0H2LUW4 (VPARA_65850) encodes the 818-residue membrane-bound PQQ-dependent quinoprotein glucose dehydrogenase Gcd responsible for periplasmic oxidation of D-glucose to D-glucono-1,5-lactone.
file:VARPS/fetP/fetP-ai-review.yaml
Variovorax paradoxus S110 fetP gene review
C5CNX5 (Vapar_2982) encodes the 90-residue cytosolic YggX-family probable Fe(2+)-trafficking protein FetP.
file:VARPD/ppk/ppk-ai-review.yaml
Variovorax paradoxus ppk gene review
A0A0H2M4T4 (VPARA_28600) encodes the 710-residue polyphosphate kinase 1 Ppk, which synthesizes inorganic polyphosphate polymers from ATP in the cytosol.
file:VARPD/ppx/ppx-ai-review.yaml
Variovorax paradoxus ppx gene review
A0A0H2MBK5 (VPARA_10490) encodes the 506-residue cytosolic exopolyphosphatase Ppx (EC 3.6.1.11) that hydrolyzes inorganic polyphosphate chains into orthophosphate.
Processive hydrolytic cleavage of terminal orthophosphate residues from inorganic polyphosphate chains in the cytosol, balancing Ppk-mediated polyphosphate synthesis.
file:VARPD/czcA3/czcA3-ai-review.yaml
Variovorax paradoxus czcA3 gene review
A0A0H2MBF7 (VPARA_44890) encodes the 1067-residue inner-membrane HME-RND cation efflux antiporter subunit CzcA3.
file:VARPD/czcB/czcB-ai-review.yaml
Variovorax paradoxus czcB gene review
A0A0H2LX82 (VPARA_44900) encodes the 455-residue periplasmic membrane-fusion adaptor subunit CzcB encoded immediately downstream of czcA3 (VPARA_44890).
Periplasmic membrane-fusion structural adaptor subunit of the tripartite CzcCBA heavy-metal efflux complex that physically bridges the inner-membrane RND antiporter CzcA3 (VPARA_44890) and the outer-membrane channel CzcC (VPARA_44910) to contribute to transmembrane metal cation export.
file:VARPD/czcC/czcC-ai-review.yaml
Variovorax paradoxus czcC gene review
A0A0H2M0U4 (VPARA_44910) encodes the 445-residue outer-membrane factor efflux duct subunit CzcC of the tripartite CzcCBA complex.
Outer-membrane factor (OMF) channel subunit of the tripartite CzcCBA heavy-metal efflux complex that forms the outer-membrane exit duct for transmembrane export of monoatomic metal cations.
file:VARPD/czcD/czcD-ai-review.yaml
Variovorax paradoxus czcD gene review
A0A0H2M558 (VPARA_15480) encodes the 320-residue inner-membrane cation diffusion facilitator (CDF) heavy-metal/H(+) antiporter CzcD.
Inner-membrane Cation Diffusion Facilitator (CDF) antiporter that catalyzes transmembrane export of cytoplasmic Zn(2+) (as well as Co(2+) and Cd(2+)) across the plasma membrane to maintain intracellular zinc ion homeostasis.
file:VARPD/cadA2/cadA2-ai-review.yaml
Variovorax paradoxus cadA2 gene review
A0A0H2LVW9 (VPARA_44980) encodes the 759-residue inner-membrane P1B-type Zn(2+)/Cd(2+)-translocating efflux ATPase CadA2 in the heavy-metal resistance island on contig JZWI01000024.
It couples ATP hydrolysis to active export of cytoplasmic Zn(2+) and Cd(2+) across the plasma membrane into the periplasm.
file:VARPD/czcI/czcI-ai-review.yaml
Variovorax paradoxus czcI gene review
A0A0H2LVR9 (VPARA_44920) encodes the 123-residue periplasmic heavy-metal resistance modulator CzcI encoded between czcCBA and czcR-cusS.
Periplasmic heavy-metal resistance modulator that fine-tunes expression and activity of the CzcCBA RND heavy-metal efflux complex and CzcR-CusS two-component system in response to periplasmic cadmium, zinc, and cobalt ions.
file:VARPD/czcR/czcR-ai-review.yaml
Variovorax paradoxus czcR gene review
A0A0H2LVW5 (VPARA_44930) encodes the 225-residue OmpR/PhoB-family two-component response regulator and transcription factor CzcR.
Two-component system OmpR/PhoB-family response regulator and sequence-specific cis-regulatory DNA-binding transcription factor that receives phosphoryl groups at Asp-51 from the cognate heavy-metal sensor histidine kinase CusS (VPARA_44940) and binds operator DNA via its C-terminal OmpR/PhoB-type winged-helix domain (residues 123-221) to regulate transcription of the czcCBA heavy-metal efflux operon in response to Zn2+, Cd2+, and Co2+.
file:VARPD/cusS/cusS-ai-review.yaml
Variovorax paradoxus cusS gene review
A0A0H2MBG2 (VPARA_44940) encodes the 443-residue inner-membrane two-component sensor histidine kinase CusS (CzcS) paired with CzcR.
Inner-membrane two-component sensor histidine kinase (CzcS/CusS) that senses elevated periplasmic Zn2+, Cd2+, and Co2+ concentrations via its N-terminal periplasmic domain, autophosphorylates at His-233, and transfers the phosphoryl group to its cognate response regulator CzcR (VPARA_44930) to induce the CzcCBA heavy-metal efflux system.
file:VARPD/fur1/fur1-ai-review.yaml
Variovorax paradoxus fur1 gene review
A0A0H2M8T9 (VPARA_18200) encodes the 139-residue cytosolic ferric uptake regulation protein Fur1 that senses intracellular Fe(2+) and represses iron-acquisition genes under iron sufficiency.
Under iron-replete conditions, Fe(2+)-loaded holo-Fur1 binds conserved Fur-box operator sequences in target promoters and acts as a transcriptional repressor of iron-acquisition and siderophore biosynthesis/import genes, whereas iron limitation demetallates the regulatory site and derepresses siderophore-mediated iron uptake.
file:VARPD/zur/zur-ai-review.yaml
Variovorax paradoxus zur gene review
A0A0H2LYR2 (VPARA_33720) encodes the 149-residue cytosolic Fur-family zinc uptake transcriptional repressor Zur that represses high-affinity zinc acquisition genes under zinc sufficiency.
Zn(2+)-sensing homodimeric DNA-binding transcriptional repressor that binds cis-regulatory Zur-box operator sequences under zinc-replete conditions to repress high-affinity zinc uptake genes and maintain cellular zinc ion homeostasis.
file:VARPD/copA2/copA2-ai-review.yaml
Variovorax paradoxus copA2 gene review
A0A0H2M2H3 (VPARA_21930) encodes the 747-residue inner-membrane P1B-1-type Cu(+)-translocating efflux ATPase CopA2 (EC 7.2.2.8).
Inner-membrane P1B-1-type Cu(+)-translocating efflux ATPase (EC 7.2.2.8) that couples ATP hydrolysis at Asp434 (434-DKTGTLT-440) to active export of cytoplasmic Cu(+) into the periplasm via its N-terminal HMA domain (22-MTCASCV-28) and TM6 390-CPC-392 translocation site to maintain cellular copper ion homeostasis.
10Nodes
9Parts
0Variant Sets
0Variants
15Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:variovorax_metallophore_metal_homeostasis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

14 gene-function check(s) reflected in core functions · 0 conflict(s) · 22 evidence or coverage gap(s) (36 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
gcd_dehydrogenase_activity gcd (Variovorax paradoxus)
UniProtKB:A0A0H2LUW4
Family Representative 		quinoprotein glucose dehydrogenase activity
GO:0008876 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fetP_ferrous_binding_activity fetP (Variovorax paradoxus S110)
UniProtKB:C5CNX5
Family Representative 		iron ion binding
GO:0005506 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fur1_transcriptional_repressor_activity fur1 (Variovorax paradoxus)
UniProtKB:A0A0H2M8T9
Family Representative 		DNA-binding transcription repressor activity
GO:0001217 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
zur_transcriptional_repressor_activity zur (Variovorax paradoxus)
UniProtKB:A0A0H2LYR2
Family Representative 		DNA-binding transcription repressor activity
GO:0001217 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ppk_kinase_activity ppk (Variovorax paradoxus)
UniProtKB:A0A0H2M4T4
Family Representative 		polyphosphate kinase activity
GO:0008976 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ppx_exopolyphosphatase_activity ppx (Variovorax paradoxus)
UniProtKB:A0A0H2MBK5
Family Representative 		exopolyphosphatase activity
GO:0004309 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
czcA3_antiporter_activity czcA3 (Variovorax paradoxus)
UniProtKB:A0A0H2MBF7
Family Representative 		monoatomic cation transmembrane transporter activity
GO:0008324 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
czcB_membrane_fusion_activity czcB (Variovorax paradoxus)
UniProtKB:A0A0H2LX82
Family Representative 		structural molecule activity
GO:0005198 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
czcC_outer_membrane_channel_activity czcC (Variovorax paradoxus)
UniProtKB:A0A0H2M0U4
Family Representative 		efflux transmembrane transporter activity
GO:0015562 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
czcD_cdf_antiporter_activity czcD / antiporter (Variovorax paradoxus)
UniProtKB:A0A0H2M558
Family Representative 		zinc ion transmembrane transporter activity
GO:0005385 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cadA2_p_type_atpase_activity cadA2 (Variovorax paradoxus)
UniProtKB:A0A0H2LVW9
Family Representative 		P-type zinc transporter activity
GO:0016463 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
copA2_p_type_atpase_activity copA2 (Variovorax paradoxus), P-type Cu(+) transporter
UniProtKB:A0A0H2M2H3
Family Representative 		P-type monovalent copper transporter activity
GO:0140581 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cusS_sensor_kinase_activity cusS (Variovorax paradoxus)
UniProtKB:A0A0H2MBG2
Family Representative 		phosphorelay sensor kinase activity
GO:0000155 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
czcR_response_regulator_activity czcR (Variovorax paradoxus)
UniProtKB:A0A0H2LVW5
Family Representative 		phosphorelay response regulator activity
GO:0000156 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gcd_dehydrogenase_activity bacterial membrane-bound PQQ-dependent glucose dehydrogenases
NCBIfam:TIGR03074
Family 		quinoprotein glucose dehydrogenase activity
GO:0008876 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR03074.
gcd_dehydrogenase_activity bacterial membrane-bound PQQ-dependent glucose dehydrogenases
InterPro:IPR017511
Family 		quinoprotein glucose dehydrogenase activity
GO:0008876 		Family Review Missing
No supported structured family review is available for InterPro:IPR017511.
fetP_ferrous_binding_activity YggX/FetP Fe(2+)-trafficking proteins
InterPro:IPR007457
Family 		iron ion binding
GO:0005506 		Family Review Missing
No supported structured family review is available for InterPro:IPR007457.
fur1_transcriptional_repressor_activity bacterial Fur ferric uptake transcriptional regulators
NCBIfam:NF006999
Family 		DNA-binding transcription repressor activity
GO:0001217 		Family Review Missing
No supported structured family review is available for NCBIfam:NF006999.
fur1_transcriptional_repressor_activity bacterial Fur ferric uptake transcriptional regulators
InterPro:IPR002481
Family 		DNA-binding transcription repressor activity
GO:0001217 		Family Review Missing
No supported structured family review is available for InterPro:IPR002481.
zur_transcriptional_repressor_activity bacterial Zur zinc uptake transcriptional regulators
InterPro:IPR002481
Family 		DNA-binding transcription repressor activity
GO:0001217 		Family Review Missing
No supported structured family review is available for InterPro:IPR002481.
ppk_kinase_activity PPK1-family polyphosphate kinases
NCBIfam:TIGR03705
Family 		polyphosphate kinase activity
GO:0008976 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR03705.
ppk_kinase_activity PPK1-family polyphosphate kinases
InterPro:IPR003414
Family 		polyphosphate kinase activity
GO:0008976 		Family Review Missing
No supported structured family review is available for InterPro:IPR003414.
ppx_exopolyphosphatase_activity Ppx/GppA-family bacterial exopolyphosphatases
InterPro:IPR030673
Family 		exopolyphosphatase activity
GO:0004309 		Family Review Missing
No supported structured family review is available for InterPro:IPR030673.
czcA3_antiporter_activity CzcA/CusA-family HME-RND heavy-metal efflux pumps
InterPro:IPR004763
Family 		monoatomic cation transmembrane transporter activity
GO:0008324 		Family Review Missing
No supported structured family review is available for InterPro:IPR004763.
czcB_membrane_fusion_activity CzcB/CusB-family periplasmic HME-RND membrane-fusion proteins
Family 		structural molecule activity
GO:0005198 		Family Id Missing
The family has no identifier linking it to a curated family review.
czcC_outer_membrane_channel_activity CzcC/CusC-family outer-membrane heavy-metal efflux factor channels
Family 		efflux transmembrane transporter activity
GO:0015562 		Family Id Missing
The family has no identifier linking it to a curated family review.
czcD_cdf_antiporter_activity CzcD/YiiP-family cation diffusion facilitator heavy-metal antiporters
NCBIfam:TIGR01297
Family 		zinc ion transmembrane transporter activity
GO:0005385 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR01297.
czcD_cdf_antiporter_activity CzcD/YiiP-family cation diffusion facilitator heavy-metal antiporters
InterPro:IPR002524
Family 		zinc ion transmembrane transporter activity
GO:0005385 		Family Review Missing
No supported structured family review is available for InterPro:IPR002524.
cadA2_p_type_atpase_activity CadA/ZntA-family P1B-2-type heavy-metal-exporting ATPases
NCBIfam:TIGR01512
Family 		P-type zinc transporter activity
GO:0016463 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR01512.
cadA2_p_type_atpase_activity CadA/ZntA-family P1B-2-type heavy-metal-exporting ATPases
InterPro:IPR027256
Family 		P-type zinc transporter activity
GO:0016463 		Family Review Missing
No supported structured family review is available for InterPro:IPR027256.
copA2_p_type_atpase_activity CopA-family P1B-1-type monovalent copper-exporting ATPases
NCBIfam:TIGR01511
Family 		P-type monovalent copper transporter activity
GO:0140581 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR01511.
copA2_p_type_atpase_activity CopA-family P1B-1-type monovalent copper-exporting ATPases
InterPro:IPR027256
Family 		P-type monovalent copper transporter activity
GO:0140581 		Family Review Missing
No supported structured family review is available for InterPro:IPR027256.
cusS_sensor_kinase_activity CzcS/CusS-family heavy-metal two-component sensor histidine kinases
NCBIfam:TIGR01386
Family 		phosphorelay sensor kinase activity
GO:0000155 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR01386.
cusS_sensor_kinase_activity CzcS/CusS-family heavy-metal two-component sensor histidine kinases
InterPro:IPR006290
Family 		phosphorelay sensor kinase activity
GO:0000155 		Family Review Missing
No supported structured family review is available for InterPro:IPR006290.
czcR_response_regulator_activity CzcR/CusR-family heavy-metal two-component response regulators
NCBIfam:TIGR01387
Family 		phosphorelay response regulator activity
GO:0000156 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR01387.
czcR_response_regulator_activity CzcR/CusR-family heavy-metal two-component response regulators
InterPro:IPR006291
Family 		phosphorelay response regulator activity
GO:0000156 		Family Review Missing
No supported structured family review is available for InterPro:IPR006291.

Gene-review completeness (15/15 grounded genes reviewed)

15 complete review(s) · 0 with deep research · 0 missing review · 15 reviewed but lacking deep research

Gene Review Complete Deep research
cadA2 A0A0H2LVW9 ✓ ✓ ✗
copA2 A0A0H2M2H3 ✓ ✓ ✗
cusS A0A0H2MBG2 ✓ ✓ ✗
czcA3 A0A0H2MBF7 ✓ ✓ ✗
czcB A0A0H2LX82 ✓ ✓ ✗
czcC A0A0H2M0U4 ✓ ✓ ✗
czcD A0A0H2M558 ✓ ✓ ✗
czcI A0A0H2LVR9 ✓ ✓ ✗
czcR A0A0H2LVW5 ✓ ✓ ✗
fetP C5CNX5 ✓ ✓ ✗
fur1 A0A0H2M8T9 ✓ ✓ ✗
gcd A0A0H2LUW4 ✓ ✓ ✗
ppk A0A0H2M4T4 ✓ ✓ ✗
ppx A0A0H2MBK5 ✓ ✓ ✗
zur A0A0H2LYR2 ✓ ✓ ✗

Details

Variovorax periplasmic D-gluconate production, intracellular iron trafficking, metalloregulatory repression, polyphosphate turnover, and heavy-metal cation efflux and signalingBiological Processvariovorax_metallophore_metal_homeostasis
intracellular iron ion homeostasisGO:0006879 monoatomic cation transmembrane transportGO:0098655

Groups six metabolic, polyphosphate, and metal-homeostasis subsystems in Variovorax paradoxus (module_type: BIOLOGICAL_PROCESS): (1) periplasmic D-glucose oxidation to D-glucono-1,5-lactone by membrane-bound PQQ-dependent glucose dehydrogenase (Gcd, A0A0H2LUW4, VPARA_65850); (2) cytosolic ferrous iron binding and intracellular iron trafficking by the YggX-family protein FetP (C5CNX5, Vapar_2982); (3) Fe(2+)- and Zn(2+)-responsive transcriptional repression of iron- and zinc-uptake operons under metal sufficiency by Fur1 (A0A0H2M8T9, VPARA_18200) and Zur (A0A0H2LYR2, VPARA_33720); (4) cytoplasmic inorganic polyphosphate synthesis by polyphosphate kinase 1 (Ppk, A0A0H2M4T4, VPARA_28600) and hydrolytic depolymerization by exopolyphosphatase (Ppx, A0A0H2MBK5, VPARA_10490; high-affinity orthophosphate uptake by PstSACB is modeled separately in MODULE:bacterial_pst_phosphate_uptake); (5) trans-envelope and inner-membrane heavy-metal cation efflux mediated by the tripartite CzcCBA HME-RND complex — CzcA3 (A0A0H2MBF7, VPARA_44890), CzcB (A0A0H2LX82, VPARA_44900), and CzcC (A0A0H2M0U4, VPARA_44910) — together with the inner-membrane CzcD CDF antiporter (A0A0H2M558, VPARA_15480) and the inner-membrane P1B-type Zn(2+)/Cd(2+) and Cu(+) efflux ATPases CadA2 (A0A0H2LVW9, VPARA_44980) and CopA2 (A0A0H2M2H3, VPARA_21930); and (6) periplasmic heavy-metal modulation by CzcI (A0A0H2LVR9, VPARA_44920) and His-Asp phosphorelay regulation by the CusS-CzcR two-component system (A0A0H2MBG2, VPARA_44940; A0A0H2LVW5, VPARA_44930). Because these six subsystems act in distinct physiological pathways across the cell envelope and cytoplasm, no sequential causal connections are asserted between the six top-level parts.

Part 1: periplasmic PQQ-dependent oxidation of D-glucose to D-glucono-1,5-lactone
Gcd periplasmic PQQ-dependent glucose oxidationReactiongcd_bioleaching_step

Annotons

Gcd quinoprotein glucose dehydrogenase
gcd_dehydrogenase_activity
Participant: Family: bacterial membrane-bound PQQ-dependent glucose dehydrogenases
Family:
bacterial membrane-bound PQQ-dependent glucose dehydrogenases
Representative Members: gcd (Variovorax paradoxus)UniProtKB:A0A0H2LUW4

Function

quinoprotein glucose dehydrogenase activityGO:0008876
Substrates: D-glucose ubiquinone
Products: D-glucono-1,5-lactone ubiquinol

Catalyzes the direct periplasmic oxidation of D-glucose to D-glucono-1,5-lactone (which hydrolyzes to D-gluconate) coupled to membrane ubiquinone reduction.

Part 2: cytosolic ferrous iron binding and intracellular iron trafficking
FetP cytosolic Fe(2+) binding and intracellular iron traffickingMolecular FunctionfetP_iron_trafficking_step

Annotons

FetP iron ion binding
fetP_ferrous_binding_activity
Participant: Family: YggX/FetP Fe(2+)-trafficking proteins
Family:
YggX/FetP Fe(2+)-trafficking proteins
Representative Members: fetP (Variovorax paradoxus S110)UniProtKB:C5CNX5

Function

iron ion bindingGO:0005506

Predicted to bind intracellular Fe(2+) in the cytosol to mediate iron transactions between iron acquisition and Fe-S cluster synthesis or repair.

Part 3: Fe(2+)- and Zn(2+)-responsive transcriptional repression of metal-uptake operons by Fur1 and Zur
Fur1 and Zur metalloregulatory transcriptional repressionRegulatory Stepfur1_zur_metalloregulatory_repression_step

Annotons

Fur1 Fe(2+)-sensing transcriptional repressor
fur1_transcriptional_repressor_activity
Participant: Family: bacterial Fur ferric uptake transcriptional regulators
Family:
bacterial Fur ferric uptake transcriptional regulators
Representative Members: fur1 (Variovorax paradoxus)UniProtKB:A0A0H2M8T9

Function

DNA-binding transcription repressor activityGO:0001217

Binds intracellular Fe(2+) under iron-replete conditions and represses transcription of siderophore biosynthesis and TonB-dependent ferric-siderophore uptake operons to maintain intracellular iron homeostasis.

Zur Zn(2+)-sensing transcriptional repressor
zur_transcriptional_repressor_activity
Participant: Family: bacterial Zur zinc uptake transcriptional regulators
Family:
bacterial Zur zinc uptake transcriptional regulators
Representative Members: zur (Variovorax paradoxus)UniProtKB:A0A0H2LYR2

Function

DNA-binding transcription repressor activityGO:0001217

Binds intracellular Zn(2+) under zinc-replete conditions and represses transcription of high-affinity zinc uptake operons to maintain cellular zinc ion homeostasis.

Part 4: cytoplasmic ATP-dependent polymerization and hydrolytic turnover of inorganic polyphosphate
Ppk and Ppx cytoplasmic inorganic polyphosphate turnoverReactionppk_polyphosphate_sequestration_step

Annotons

Ppk polyphosphate kinase
ppk_kinase_activity
Participant: Family: PPK1-family polyphosphate kinases
Family:
PPK1-family polyphosphate kinases
Representative Members: ppk (Variovorax paradoxus)UniProtKB:A0A0H2M4T4

Function

polyphosphate kinase activityGO:0008976
Substrates: ATP polyphosphate
Products: ADP polyphosphate

Catalyzes the reversible transfer of the terminal gamma-phosphate of ATP to form long-chain inorganic polyphosphate in the cytoplasm.

Ppx exopolyphosphatase
ppx_exopolyphosphatase_activity
Participant: Family: Ppx/GppA-family bacterial exopolyphosphatases
Family:
Ppx/GppA-family bacterial exopolyphosphatases
Representative Members: ppx (Variovorax paradoxus)UniProtKB:A0A0H2MBK5

Function

exopolyphosphatase activityGO:0004309
Substrates: polyphosphate water
Products: polyphosphate phosphate

Catalyzes the processive hydrolytic release of terminal orthophosphate (Pi) from inorganic polyphosphate chains in the cytosol, balancing Ppk-mediated polyP synthesis.

Part 5: trans-envelope CzcCBA HME-RND, inner-membrane CzcD CDF, and inner-membrane CadA2/CopA2 P1B-type ATPase heavy-metal cation efflux
CzcCBA tripartite RND, CzcD CDF, and CadA2/CopA2 P1B-type ATPase heavy-metal cation effluxTransport StepczcA3_heavy_metal_efflux_step

Annotons

CzcA3 inner-membrane RND heavy-metal cation antiporter
czcA3_antiporter_activity
Participant: Family: CzcA/CusA-family HME-RND heavy-metal efflux pumps
Family:
CzcA/CusA-family HME-RND heavy-metal efflux pumps
Representative Members: czcA3 (Variovorax paradoxus)UniProtKB:A0A0H2MBF7

Function

monoatomic cation transmembrane transporter activityGO:0008324

Couples the inner-membrane proton-motive force to transmembrane export of divalent metal cations (Co2+, Zn2+, Cd2+) as the inner-membrane RND pump subunit of the tripartite CzcCBA complex.

CzcB periplasmic membrane-fusion adaptor subunit
czcB_membrane_fusion_activity
Participant: Family: CzcB/CusB-family periplasmic HME-RND membrane-fusion proteins
Family:
CzcB/CusB-family periplasmic HME-RND membrane-fusion proteins
Representative Members: czcB (Variovorax paradoxus)UniProtKB:A0A0H2LX82

Function

structural molecule activityGO:0005198

Acts as the periplasmic structural membrane-fusion adaptor that bridges the inner-membrane RND pump CzcA3 and the outer-membrane channel CzcC across the periplasm, contributing to tripartite CzcCBA efflux transmembrane transporter activity (GO:0015562).

CzcC outer-membrane efflux factor channel subunit
czcC_outer_membrane_channel_activity
Participant: Family: CzcC/CusC-family outer-membrane heavy-metal efflux factor channels
Family:
CzcC/CusC-family outer-membrane heavy-metal efflux factor channels
Representative Members: czcC (Variovorax paradoxus)UniProtKB:A0A0H2M0U4

Function

efflux transmembrane transporter activityGO:0015562

Forms the trimeric outer-membrane beta-barrel/alpha-helical tunnel that conducts metal cations from CzcA3-CzcB across the outer membrane to the extracellular medium.

CzcD inner-membrane CDF heavy-metal/H(+) antiporter
czcD_cdf_antiporter_activity
Participant: Family: CzcD/YiiP-family cation diffusion facilitator heavy-metal antiporters
Family:
CzcD/YiiP-family cation diffusion facilitator heavy-metal antiporters
Representative Members: czcD / antiporter (Variovorax paradoxus)UniProtKB:A0A0H2M558

Function

zinc ion transmembrane transporter activityGO:0005385

Exports cytoplasmic Zn(2+), Co(2+), and Cd(2+) across the inner membrane into the periplasm in exchange for protons, where cations are subsequently extruded across the outer membrane by CzcCBA.

CadA2 inner-membrane P1B-type Zn(2+)/Cd(2+)-exporting ATPase
cadA2_p_type_atpase_activity
Participant: Family: CadA/ZntA-family P1B-2-type heavy-metal-exporting ATPases
Family:
CadA/ZntA-family P1B-2-type heavy-metal-exporting ATPases
Representative Members: cadA2 (Variovorax paradoxus)UniProtKB:A0A0H2LVW9

Function

P-type zinc transporter activityGO:0016463

Couples ATP hydrolysis to active export of cytoplasmic Zn(2+) and Cd(2+) across the inner membrane into the periplasm for subsequent outer-membrane extrusion by CzcCBA.

CopA2 inner-membrane P1B-1-type Cu(+)-exporting ATPase
copA2_p_type_atpase_activity
Participant: Family: CopA-family P1B-1-type monovalent copper-exporting ATPases
Family:
CopA-family P1B-1-type monovalent copper-exporting ATPases
Representative Members: copA2 (Variovorax paradoxus), P-type Cu(+) transporterUniProtKB:A0A0H2M2H3

Function

P-type monovalent copper transporter activityGO:0140581

Couples ATP hydrolysis to active export of cytoplasmic Cu(+) across the inner membrane into the periplasm to maintain cellular copper ion homeostasis.

Part 6: periplasmic heavy-metal modulation by CzcI and CusS/CzcR His-Asp phosphorelay regulation
CzcI periplasmic modulation and CusS/CzcR phosphorelaySignaling Pathwayczc_heavy_metal_regulatory_relay

Connections

CusS transfers its phosphoryl group from His233 to the conserved Asp51 receiver aspartate of CzcR.
Part 1: periplasmic heavy-metal modulation by CzcI
CzcI periplasmic heavy-metal resistance modulationBiological Processczci_periplasmic_modulation

Annotons

CzcI periplasmic heavy-metal resistance modulator
czcI_periplasmic_modulator_activity
Participant: Family: CzcI-family periplasmic heavy-metal resistance modulators
Family:
CzcI-family periplasmic heavy-metal resistance modulators
Representative Members: czcI (Variovorax paradoxus)UniProtKB:A0A0H2LVR9

Processes

response to cadmium ionGO:0046686 response to zinc ionGO:0010043

Locations

outer membrane-bounded periplasmic spaceGO:0030288

Modulates expression and activity of the CzcCBA efflux complex and CzcR-CusS two-component system in response to periplasmic Zn(2+), Cd(2+), and Co(2+).

Part 2: CusS periplasmic heavy-metal sensor-kinase signaling
CusS (CzcS) sensor-kinase signalingBiological Processcuss_sensor_signaling

Annotons

CusS (CzcS) heavy-metal two-component sensor histidine kinase
cusS_sensor_kinase_activity
Participant: Family: CzcS/CusS-family heavy-metal two-component sensor histidine kinases
Family:
CzcS/CusS-family heavy-metal two-component sensor histidine kinases
Representative Members: cusS (Variovorax paradoxus)UniProtKB:A0A0H2MBG2

Function

phosphorelay sensor kinase activityGO:0000155

Senses elevated periplasmic Zn(2+), Cd(2+), and Co(2+), undergoes autocatalytic phosphorylation at His233, and phosphorylates CzcR to induce CzcCBA expression.

Part 3: CzcR receiver-aspartate phosphorylation and transcriptional regulation
CzcR response regulatorRegulatory Stepczcr_response_regulator

Annotons

CzcR heavy-metal two-component response regulator
czcR_response_regulator_activity
Participant: Family: CzcR/CusR-family heavy-metal two-component response regulators
Family:
CzcR/CusR-family heavy-metal two-component response regulators
Representative Members: czcR (Variovorax paradoxus)UniProtKB:A0A0H2LVW5

Function

phosphorelay response regulator activityGO:0000156

Receives phosphoryl groups from CusS at Asp51 and regulates transcription of the czcCBA heavy-metal efflux operon in response to periplasmic Zn(2+), Cd(2+), and Co(2+).