Thiamine (vitamin B1) uptake and diphosphate activation (SLC19A2/A3 -> TPK1 -> SLC25A19; THTPA)

Humans cannot synthesise thiamine (vitamin B1) and must take it up from the diet, then convert it to its active cofactor form thiamine diphosphate (ThDP, also called thiamine pyrophosphate, TPP), which is required by pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain 2-oxoacid dehydrogenase and transketolase. Free thiamine is imported across the plasma membrane by the two high-affinity SLC19 thiamine transporters THTR1 (SLC19A2) and THTR2 (SLC19A3). In the cytosol thiamine pyrophosphokinase TPK1 transfers a diphosphate group from ATP (physiologically UTP is the preferred donor) to thiamine, producing ThDP. ThDP is then delivered to the mitochondrial matrix by the inner-membrane carrier SLC25A19 to supply the matrix dehydrogenases. Cellular thiamine triphosphate (ThTP), a minor phosphorylated form, is hydrolysed back to ThDP by the cytosolic thiamine triphosphatase THTPA, contributing to phosphothiamine homeostasis. Defects in this module cause thiamine-responsive megaloblastic anaemia (SLC19A2 / Rogers syndrome), biotin-thiamine-responsive basal ganglia disease (SLC19A3), thiamine metabolism dysfunction syndrome 5 / episodic encephalopathy (TPK1) and Amish lethal microcephaly / THMD4 (SLC25A19).

MODULE:thiamine_uptake_and_activationDRAFTMetabolic Pathwaymodules/thiamine_uptake_and_activation.yaml
thiamine metabolic processGO:0006772 thiamine transportGO:0015888 thiamine diphosphate biosynthetic processGO:0009229
GO:0006772
thiamine metabolic process
The module covers thiamine uptake, activation to ThDP, and phosphothiamine homeostasis (GO:0006772).
GO:0015888
thiamine transport
SLC19A2/SLC19A3 import thiamine across the plasma membrane (GO:0015888).
GO:0009229
thiamine diphosphate biosynthetic process
TPK1 produces the active cofactor thiamine diphosphate (GO:0009229).
file:human/SLC19A2/SLC19A2-ai-review.yaml
SLC19A2 gene review (human)
Plasma-membrane thiamine transporter THTR1 (UniProtKB:O60779, GO:0015234) matches the completed human SLC19A2 review.
file:human/SLC19A3/SLC19A3-ai-review.yaml
SLC19A3 gene review (human)
Plasma-membrane thiamine transporter THTR2 (UniProtKB:Q9BZV2, GO:0015234) matches the completed human SLC19A3 review.
file:human/TPK1/TPK1-ai-review.yaml
TPK1 gene review (human)
Thiamine pyrophosphokinase (UniProtKB:Q9H3S4, GO:0004788) matches the completed human TPK1 review.
file:human/SLC25A19/SLC25A19-ai-review.yaml
SLC25A19 gene review (human)
Mitochondrial ThDP carrier (UniProtKB:Q9HC21, GO:0090422) matches the completed human SLC25A19 review.
file:human/THTPA/THTPA-ai-review.yaml
THTPA gene review (human)
Cytosolic thiamine triphosphatase (UniProtKB:Q9BU02, GO:0050333) matches the completed human THTPA review.
5Nodes
4Parts
0Variant Sets
0Variants
4Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:thiamine_uptake_and_activation 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

5 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (9 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
slc19_uptake SLC19A2 (human; THTR1)
UniProtKB:O60779
Family Representative 		thiamine transmembrane transporter activity
GO:0015234 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc19_uptake SLC19A3 (human; THTR2)
UniProtKB:Q9BZV2
Family Representative 		thiamine transmembrane transporter activity
GO:0015234 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tpk1_activity TPK1 (human)
UniProtKB:Q9H3S4
Family Representative 		thiamine diphosphokinase activity
GO:0004788 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc25a19_activity SLC25A19 (human)
UniProtKB:Q9HC21
Family Representative 		thiamine pyrophosphate transmembrane transporter activity
GO:0090422 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
thtpa_activity THTPA (human)
UniProtKB:Q9BU02
Family Representative 		thiamine triphosphate phosphatase activity
GO:0050333 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc19_uptake SLC19 thiamine/folate transporter family
PANTHER:PTHR10686
Family 		thiamine transmembrane transporter activity
GO:0015234 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10686.
tpk1_activity TPK1 / thiamine pyrophosphokinase family
PANTHER:PTHR13622
Family 		thiamine diphosphokinase activity
GO:0004788 		Family Supported
Family review supports GO:0004788 FAMILY_WIDE. Asserted by thiamine_uptake_and_activation and eukaryotic_thiamine_biosynthesis; accepted by THI80, tnr3 and TPK1.
slc25a19_activity SLC25 mitochondrial carrier family
PANTHER:PTHR24089
Family 		thiamine pyrophosphate transmembrane transporter activity
GO:0090422 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR24089.
thtpa_activity THTPA / CYTH triphosphate-tunnel metalloenzyme family
PANTHER:PTHR14586
Family 		thiamine triphosphate phosphatase activity
GO:0050333 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR14586.

Gene-review completeness (5/5 grounded genes reviewed)

5 complete review(s) · 0 with deep research · 0 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
SLC19A2 O60779 ✓ ✓ ✗
SLC19A3 Q9BZV2 ✓ ✓ ✗
SLC25A19 Q9HC21 ✓ ✓ ✗
THTPA Q9BU02 ✓ ✓ ✗
TPK1 Q9H3S4 ✓ ✓ ✗

Details

Context
plasma membraneGO:0005886 cytosolGO:0005829 mitochondrial inner membraneGO:0005743
Thiamine (vitamin B1) uptake and activationMetabolic Pathwaythiamine_uptake_and_activation
thiamine metabolic processGO:0006772 thiamine transportGO:0015888 thiamine diphosphate biosynthetic processGO:0009229
Context
plasma membraneGO:0005886 cytosolGO:0005829 mitochondrial inner membraneGO:0005743

Thiamine (vitamin B1) uptake and diphosphate activation (GO:0006772), grounded to five completed human gene reviews. Humans are thiamine auxotrophs: uptake -> plasma-membrane SLC19A2/THTR1 (O60779) + SLC19A3/THTR2 (Q9BZV2), both PTHR10686 (thiamine-specific SLC19 members; the paralog SLC19A1 is a folate carrier), GO:0015234 H+/thiamine antiport; activation -> cytosolic TPK1 (Q9H3S4 PTHR13622) transfers PPi from ATP (human prefers UTP; GO:0141200) to thiamine -> ThDP (GO:0004788/GO:0009229); distribution -> mitochondrial inner-membrane carrier SLC25A19 (Q9HC21 PTHR24089, GO:0090422, already reviewed) imports ThDP to the matrix dehydrogenases; homeostasis -> cytosolic THTPA (Q9BU02 PTHR14586, GO:0050333) hydrolyses the minor ThTP pool back to ThDP. ThDP is the cofactor for PDH, OGDH, BCKDH and transketolase. Both SLC19A2 and SLC19A3 also show secondary pyridoxine transport (kept non-core); neither transports folate (SLC19A2 wrong folic-acid-transport IEA removed) nor biotin (Reactome states no biotin affinity for SLC19A3, despite BTBGD's biotin-responsiveness). Diseases: SLC19A2 = TRMA/Rogers, SLC19A3 = BTBGD, TPK1 = THMD5, SLC25A19 = Amish lethal microcephaly/THMD4. GO term ids/labels verified against the local go.db; module passes structural + term-label validation.

Connections

thiamine_uptake -> thiamine_activation Provides Input For
Imported cytosolic thiamine is the substrate for TPK1.
thiamine_activation -> mito_thdp_import Provides Input For
TPK1-made ThDP is imported into mitochondria by SLC25A19.
thtp_homeostasis -> mito_thdp_import Provides Input For
THTPA regenerates ThDP from ThTP, contributing to the cytosolic ThDP pool.
Part 1: plasma-membrane thiamine uptake
Thiamine transporters (SLC19A2/THTR1, SLC19A3/THTR2)Reactionthiamine_uptake

Annotons

SLC19A2/SLC19A3: thiamine transmembrane transporter
slc19_uptake
Participant: Family: SLC19 thiamine/folate transporter family
Family:
SLC19 thiamine/folate transporter familyPANTHER:PTHR10686
Representative Members: SLC19A2 (human; THTR1)UniProtKB:O60779 SLC19A3 (human; THTR2)UniProtKB:Q9BZV2

Function

thiamine transmembrane transporter activityGO:0015234
Substrates: thiamine (extracellular; H+ antiport)
Products: thiamine (cytosolic)

Locations

plasma membraneGO:0005886

Import dietary thiamine across the plasma membrane into the cytosol.

Part 2: thiamine -> thiamine diphosphate (activation)
Thiamine pyrophosphokinase (TPK1)Reactionthiamine_activation

Annotons

TPK1: thiamine diphosphokinase
tpk1_activity
Participant: Family: TPK1 / thiamine pyrophosphokinase family
Family:
TPK1 / thiamine pyrophosphokinase familyPANTHER:PTHR13622
Representative Members: TPK1 (human)UniProtKB:Q9H3S4

Function

thiamine diphosphokinase activityGO:0004788
Substrates: thiamine ATP (UTP preferred in human; Mg2+)
Products: thiamine diphosphate (ThDP / TPP) AMP

Locations

cytosolGO:0005829

Pyrophosphorylate thiamine to the active cofactor ThDP.

Part 3: mitochondrial ThDP import
Mitochondrial thiamine pyrophosphate carrier (SLC25A19)Reactionmito_thdp_import

Annotons

SLC25A19: mitochondrial ThDP carrier
slc25a19_activity
Participant: Family: SLC25 mitochondrial carrier family
Family:
SLC25 mitochondrial carrier familyPANTHER:PTHR24089
Representative Members: SLC25A19 (human)UniProtKB:Q9HC21

Function

thiamine pyrophosphate transmembrane transporter activityGO:0090422
Substrates: thiamine diphosphate (cytosolic)
Products: thiamine diphosphate (mitochondrial matrix)

Locations

mitochondrial inner membraneGO:0005743

Deliver ThDP into the mitochondrial matrix.

Part 4: thiamine triphosphate homeostasis
Thiamine triphosphatase (THTPA)Reactionthtp_homeostasis

Annotons

THTPA: thiamine triphosphatase
thtpa_activity
Participant: Family: THTPA / CYTH triphosphate-tunnel metalloenzyme family
Family:
THTPA / CYTH triphosphate-tunnel metalloenzyme familyPANTHER:PTHR14586
Representative Members: THTPA (human)UniProtKB:Q9BU02

Function

thiamine triphosphate phosphatase activityGO:0050333
Substrates: thiamine triphosphate (ThTP) H2O
Products: thiamine diphosphate (ThDP) phosphate

Locations

cytosolGO:0005829

Hydrolyze thiamine triphosphate to ThDP, maintaining phosphothiamine homeostasis.