Urea cycle (vertebrate hepatic ureagenesis, Krebs-Henseleit cycle)

The urea cycle (ornithine cycle / Krebs-Henseleit cycle) is the principal pathway for the detoxification of waste nitrogen in ureotelic vertebrates, converting ammonia (arising largely from amino-acid catabolism) plus bicarbonate and aspartate-derived nitrogen into urea for renal excretion. In mammals it operates predominantly in periportal hepatocytes and spans two compartments: the first two committed steps are mitochondrial and the last three are cytosolic, so the pathway is physically split across the inner mitochondrial membrane and requires two dedicated mitochondrial carriers. The cycle proper comprises six enzymes. N-acetylglutamate synthase (NAGS) produces N-acetyl-L-glutamate (NAG), the obligate allosteric activator of carbamoyl phosphate synthetase 1 and therefore the regulatory gate of the whole pathway. Carbamoyl phosphate synthetase 1 (CPS1) condenses ammonia, bicarbonate and two ATP into carbamoyl phosphate in the matrix. Ornithine transcarbamylase (OTC) transfers the carbamoyl group to L-ornithine to give L-citrulline. Citrulline is exported to the cytosol in exchange for ornithine by the mitochondrial ornithine/citrulline carrier SLC25A15 (ORNT1). In the cytosol argininosuccinate synthase (ASS1) condenses citrulline with L-aspartate (the second nitrogen donor, supplied to the cytosol by the citrin aspartate/glutamate carrier SLC25A13) at the expense of ATP to form argininosuccinate; argininosuccinate lyase (ASL) cleaves this to L-arginine and fumarate; and arginase 1 (ARG1) hydrolyses arginine to urea and L-ornithine, regenerating the ornithine that re-enters mitochondria to close the cycle. The fumarate released by ASL links the urea cycle to the TCA cycle and, via aspartate regeneration, to the "aspartate-argininosuccinate shunt". Inherited deficiency of any of the six enzymes, of the two transporters (SLC25A15, SLC25A13), or of NAGS causes a urea cycle disorder presenting with hyperammonemia. The same enzyme chemistry, used biosynthetically rather than for nitrogen disposal, also produces arginine de novo (the arginine biosynthetic pathway) in tissues and organisms lacking a complete ureotelic cycle.

MODULE:urea_cycleDRAFTMetabolic Pathwaymodules/urea_cycle.yaml
urea cycleGO:0000050
GO:0000050
urea cycle
The module is grounded in the GO biological-process term for the urea cycle; every enzyme and transporter step is annotated to (or acts within) GO:0000050.
Reactome:R-HSA-70635
Urea cycle
The step order, compartmentalization and reaction stoichiometries follow the human Reactome "Urea cycle" pathway (R-HSA-70635) and its member reactions (R-HSA-70542, R-HSA-70555, R-HSA-70560, R-HSA-70634, R-HSA-70577, R-HSA-70573, R-HSA-70569, R-HSA-372448).
file:human/NAGS/NAGS-ai-review.yaml
NAGS gene review (human)
The NAGS regulatory-step grounding (UniProtKB:Q8N159, GO:0004042, EC 2.3.1.1, mitochondrial matrix) matches the completed human NAGS review.
file:human/CPS1/CPS1-ai-review.yaml
CPS1 gene review (human)
The CPS1 step grounding (UniProtKB:P31327, GO:0004087 carbamoyl-phosphate synthase (ammonia) activity, GO:0000050 urea cycle, mitochondrial matrix) matches the completed human CPS1 review, which established the ammonia-dependent (not glutamine-hydrolyzing) chemistry.
file:human/OTC/OTC-ai-review.yaml
OTC gene review (human)
The OTC step grounding (UniProtKB:P00480, GO:0004585 ornithine carbamoyltransferase activity, GO:0000050 urea cycle, mitochondrial matrix) matches the completed human OTC review.
file:human/SLC25A15/SLC25A15-ai-review.yaml
SLC25A15 gene review (human)
The ornithine/citrulline transport step (UniProtKB:Q9Y619, GO:0000064 L-ornithine transmembrane transporter activity, mitochondrial inner membrane) matches the completed human SLC25A15/ORNT1 review.
file:human/ASS1/ASS1-ai-review.yaml
ASS1 gene review (human)
The ASS1 step grounding (UniProtKB:P00966, GO:0004055 argininosuccinate synthase activity, GO:0000050 urea cycle, cytosol) matches the completed human ASS1 review.
file:human/ASL/ASL-ai-review.yaml
ASL gene review (human)
The ASL step grounding (UniProtKB:P04424, GO:0004056 argininosuccinate lyase activity, GO:0000050 urea cycle, cytosol) matches the completed human ASL review, which also captures ASL's catalysis-independent NOS scaffold role.
file:human/ARG1/ARG1-ai-review.yaml
ARG1 gene review (human)
The ARG1 terminal-step grounding (UniProtKB:P05089, GO:0004053 arginase activity, GO:0000050 urea cycle, cytosol) matches the completed human ARG1 review.
file:human/SLC25A13/SLC25A13-ai-review.yaml
SLC25A13 gene review (human)
The citrin aspartate-supply step (UniProtKB:Q9UJS0, GO:0000515 aspartate:glutamate proton antiporter activity, mitochondrial inner membrane) matches the completed human SLC25A13 review, which added the urea-cycle (GO:0000050) involvement.
9Nodes
8Parts
0Variant Sets
0Variants
8Annotons
8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:urea_cycle 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

10 gene-function check(s) reflected in core functions · 0 conflict(s) · 5 evidence or coverage gap(s) (19 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
nags_activity NAGS (human, mitochondrial)
UniProtKB:Q8N159
Family Representative 		L-glutamate N-acetyltransferase activity, acting on acetyl-CoA as donor
GO:0004042 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cps1_activity CPS1 (human, mitochondrial)
UniProtKB:P31327
Family Representative 		carbamoyl-phosphate synthase (ammonia) activity
GO:0004087 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
otc_activity OTC (human, mitochondrial)
UniProtKB:P00480
Family Representative 		ornithine carbamoyltransferase activity
GO:0004585 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc25a15_activity SLC25A15 / ORNT1 (human)
UniProtKB:Q9Y619
Family Representative 		L-ornithine transmembrane transporter activity
GO:0000064 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc25a15_activity SLC25A2 / ORNT2 (human paralog)
UniProtKB:Q9BXI2
Family Representative 		L-ornithine transmembrane transporter activity
GO:0000064 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
ass1_activity ASS1 (human)
UniProtKB:P00966
Family Representative 		argininosuccinate synthase activity
GO:0004055 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
asl_activity ASL (human)
UniProtKB:P04424
Family Representative 		argininosuccinate lyase activity
GO:0004056 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
arg1_activity ARG1 (human, cytosolic, hepatic)
UniProtKB:P05089
Family Representative 		arginase activity
GO:0004053 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
arg1_activity ARG2 (human, mitochondrial paralog)
UniProtKB:P78540
Family Representative 		arginase activity
GO:0004053 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc25a13_activity SLC25A13 / citrin (human, liver)
UniProtKB:Q9UJS0
Family Representative 		L-aspartate transmembrane transporter activity
GO:0015183 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc25a13_activity SLC25A12 / aralar (human paralog)
UniProtKB:O75746
Family Representative 		L-aspartate transmembrane transporter activity
GO:0015183 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nags_activity N-acetylglutamate synthase family (NAGS)
PANTHER:PTHR23342
Family 		L-glutamate N-acetyltransferase activity, acting on acetyl-CoA as donor
GO:0004042 		Family Function Unreviewed
Family review leaves GO:0004042 UNRESOLVED. Unresolved because animal NAGS has the activity but sits in SF0 together with the NAG kinases, so no subfamily list can include animal NAGS without also asserting the activity for the kinases; SUBFAMILY_ONLY is therefore not used. For animal NAGS, scope by the PAINT node PTN000597387 or by member. SF4 (fungal NAGS) has the activity, and the arginine biosynthesis module uses it with a GO:0004042 required_function. The urea cycle module selects the whole family (PANTHER:PTHR23342) for its NAGS annoton with no required_function; that selector is dominated by acetylglutamate kinases and should be narrowed. Its note that the family "spans bacterial ArgA-type" enzymes is also inaccurate: the bacterial members are ArgB-type kinases, and bacterial ArgA is not in this family.
cps1_activity Carbamoyl-phosphate synthase (ammonia) family (CPS1)
PANTHER:PTHR11405:SF53
Family 		carbamoyl-phosphate synthase (ammonia) activity
GO:0004087 		Family Supported
Family review supports GO:0004087 for PANTHER:PTHR11405:SF53. Ammonia-dependent carbamoyl-phosphate synthesis is the intrinsic activity of the synthetase domains, present in the SF53 large chains and the SF5 CAD-type proteins. SF4 small chains lack those domains. Split archaeal CarB halves carry only one of the two ATP-grasp halves and are excepted, because the activity needs both halves.
otc_activity Ornithine/aspartate carbamoyltransferase family (OTC)
PANTHER:PTHR45753
Family 		ornithine carbamoyltransferase activity
GO:0004585 		Family Scope Restricted
GO:0004585 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Safe for the OTC subfamilies SF1 to SF4 (anabolic and catabolic enzymes alike), not for SF6 aspartate carbamoyltransferases. Within SF3, YgeW and the N-succinylornithine and putrescine carbamoyltransferases are exceptions. The arginine biosynthesis module selects SF3. This contains the yeast, human and many bacterial anabolic OTCs, but not E. coli ArgF/ArgI (SF4). The urea cycle module selects the whole family, which also includes the PyrB aspartate carbamoyltransferases.
slc25a15_activity Mitochondrial basic-amino-acid (ornithine) carrier family (SLC25A15/SLC25A2)
PANTHER:PTHR45624
Family 		L-ornithine transmembrane transporter activity
GO:0000064 		Family Scope Restricted
GO:0000064 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Ornithine carriers: SF22 (SLC25A15), SF20 (SLC25A2) and SF31 (ORT1, arg-13). PTN000641358 also propagates it to Arabidopsis BOU and Dictyostelium mcfS/mcfY (SF12), plant BAC1 (SF15) and Dictyostelium mcfD/mcfL, which were not reviewed here; S. pombe SPAC4G9.20c (Q10248, also SF12) does not receive it because it sits under the fungal IRD. Not the carnitine carriers. The urea cycle module uses the whole family PANTHER:PTHR45624 for this activity; SF22/SF20 or the node PTN000641358 would be the correct scope. SF31 is listed because ORT1 and arg-13 are experimental ornithine carriers, despite the PAINT IRD at PTN001183566.
ass1_activity Argininosuccinate synthase family (ASS1)
PANTHER:PTHR11587
Family 		argininosuccinate synthase activity
GO:0004055 		Family Supported
Family review supports GO:0004055 FAMILY_WIDE. All 607 Swiss-Prot members in entries.csv are named argininosuccinate synthases except one, the Aspergillus lentulus nitB protein (A0AAN4PT81, "argininosuccinate synthetase-like"), whose activity has not been assessed; no member has evidence of lost activity. Seeds span bacteria, fungi and animals, and every reviewed module member accepts the activity.
asl_activity Argininosuccinate lyase / fumarase superfamily (ASL)
PANTHER:PTHR43814
Family 		argininosuccinate lyase activity
GO:0004056 		Family Supported
Family review supports GO:0004056 FAMILY_WIDE. Every enzymatic Swiss-Prot member in entries.csv (624, all SF1) is named an argininosuccinate lyase, a bifunctional ArgH/ArgHA fusion that retains the lyase domain, or a probable lyase (S. pombe arg41). Chicken delta-1 crystallin is excepted on the PAINT IKR, and duck delta-1 crystallin (P24057) on direct assays; duck delta-2 crystallin (P24058) keeps the activity. Turkey delta-1 crystallin (Q7SIE0) has not been assayed and is left unadjudicated.
arg1_activity Arginase / ureohydrolase family (ARG1/ARG2)
PANTHER:PTHR43782
Family 		arginase activity
GO:0004053 		Family Supported
Family review supports GO:0004053 FAMILY_WIDE. Shared by the vertebrate ARG1/ARG2, fungal and bacterial arginases. This is the term both the arginine catabolism and urea cycle modules require of the family. The one substrate-diverged member seen in the inventory, Streptomyces DcsB, is a secondary-metabolism enzyme outside any module.
slc25a13_activity Mitochondrial aspartate/glutamate carrier family (SLC25A13/SLC25A12)
PANTHER:PTHR45678
Family 		L-aspartate transmembrane transporter activity
GO:0015183 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45678.

Gene-review completeness (10/11 grounded genes reviewed)

5 complete review(s) · 8 with deep research · 1 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
ARG1 P05089 ✓ 34/38 ✓
ARG2 P78540 ✓ 41/42 ✗
ASL P04424 ✓ 27/33 ✓
ASS1 P00966 ✓ 60/80 ✓
CPS1 P31327 ✓ 69/81 ✓
NAGS Q8N159 ✓ ✓ ✓
OTC P00480 ✓ ✓ ✓
SLC25A2 / ORNT2 (human paralog) Q9BXI2 ✗ — —
SLC25A12 O75746 ✓ ✓ ✗
SLC25A13 Q9UJS0 ✓ ✓ ✓
SLC25A15 Q9Y619 ✓ ✓ ✓

Details

Context
mitochondrial matrixGO:0005759 mitochondrial inner membraneGO:0005743 cytosolGO:0005829
Urea cycleMetabolic Pathwayurea_cycle
urea cycleGO:0000050
Context
mitochondrial matrixGO:0005759 mitochondrial inner membraneGO:0005743 cytosolGO:0005829

Six-enzyme vertebrate urea cycle plus its two obligatory mitochondrial carriers, grounded to the human enzymes NAGS (UniProtKB:Q8N159, GO:0004042, EC 2.3.1.1), CPS1 (P31327, GO:0004087, EC 6.3.4.16), OTC (P00480, GO:0004585, EC 2.1.3.3), ASS1 (P00966, GO:0004055, EC 6.3.4.5), ASL (P04424, GO:0004056, EC 4.3.2.1) and ARG1 (P05089, GO:0004053, EC 3.5.3.1), with the carriers SLC25A15/ORNT1 (Q9Y619, GO:0000064) and SLC25A13/citrin (Q9UJS0, GO:0015183). Molecular-function and cellular-component GO terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step is grounded generically with a PANTHER family selector (covering paralogs and orthologs) plus concrete human representative members, and the notable human paralogs are listed where they exist (ARG2, SLC25A2/ORNT2, SLC25A12/aralar). The reaction-chaining check is not applicable here because the intermediates are amino acids / small metabolites rather than CoA thioesters. Downstream fates (fumarate to the TCA cycle; arginine to nitric-oxide synthase, creatine or polyamine synthesis) and the de novo arginine-biosynthetic use of the same enzymes are noted but out of scope for this nitrogen-disposal module.

Connections

nags_step -> cps1_step Positively Regulates
N-acetyl-L-glutamate made by NAGS is the obligate allosteric activator of CPS1; without it CPS1 is inactive, so NAGS gates entry to the cycle.
cps1_step -> otc_step Provides Input For
Carbamoyl phosphate from CPS1 is the carbamoyl donor for OTC.
Citrulline made by OTC in the matrix is exported to the cytosol by SLC25A15.
Cytosolic citrulline delivered by SLC25A15 is a substrate of ASS1.
citrin_aspartate_supply -> ass1_step Provides Input For
Citrin (SLC25A13) supplies the cytosolic aspartate that ASS1 condenses with citrulline (the second nitrogen donor).
ass1_step -> asl_step Provides Input For
Argininosuccinate from ASS1 is cleaved by ASL.
asl_step -> arg1_step Provides Input For
L-arginine from ASL is hydrolysed by ARG1.
L-ornithine regenerated by ARG1 is re-imported to the matrix by SLC25A15 (in exchange for citrulline), closing the cycle.
Part 1: regulatory step (produces the CPS1 allosteric activator)
L-glutamate + acetyl-CoA to N-acetyl-L-glutamate + CoARegulatory Stepnags_step

Annotons

NAGS: N-acetylglutamate synthase
nags_activity
Participant: Family: N-acetylglutamate synthase family (NAGS)
Family:
N-acetylglutamate synthase family (NAGS)PANTHER:PTHR23342
Representative Members: NAGS (human, mitochondrial)UniProtKB:Q8N159

Function

L-glutamate N-acetyltransferase activity, acting on acetyl-CoA as donorGO:0004042
Substrates: L-glutamate acetyl-CoA
Products: N-acetyl-L-glutamate coenzyme A

Locations

mitochondrial matrixGO:0005759

Regulatory (not stoichiometric) step of ureagenesis: synthesizes N-acetyl-L-glutamate, the obligate allosteric activator of CPS1. NAG availability gates flux through the whole cycle and rises with protein load / arginine; NAGS deficiency is pharmacologically rescuable with the NAG analogue carglumic acid. The PANTHER family spans bacterial ArgA-type and vertebrate mitochondrial NAGS orthologs; the human enzyme is subfamily PTHR23342:SF0.

Part 2: first committed step (mitochondrial carbamoyl phosphate synthesis)
NH3 + HCO3- + 2 ATP to carbamoyl phosphate + 2 ADP + PiReactioncps1_step

Annotons

CPS1: carbamoyl-phosphate synthetase 1
cps1_activity
Participant: Family: Carbamoyl-phosphate synthase (ammonia) family (CPS1)
Family:
Carbamoyl-phosphate synthase (ammonia) family (CPS1)PANTHER:PTHR11405:SF53
Representative Members: CPS1 (human, mitochondrial)UniProtKB:P31327

Function

carbamoyl-phosphate synthase (ammonia) activityGO:0004087
Substrates: ammonia hydrogencarbonate ATP
Products: carbamoyl phosphate ADP phosphate

Locations

mitochondrial matrixGO:0005759

First committed and rate-setting step: incorporates free ammonia (the primary nitrogen entering the cycle) with bicarbonate and two ATP into carbamoyl phosphate. Absolutely dependent on the NAGS product N-acetylglutamate for activity. Distinct from the cytosolic glutamine-dependent CPS II (CAD) of pyrimidine synthesis.

Part 3: carbamoyl transfer to ornithine (citrulline synthesis)
carbamoyl phosphate + L-ornithine to L-citrulline + PiReactionotc_step

Annotons

OTC: ornithine transcarbamylase
otc_activity
Participant: Family: Ornithine/aspartate carbamoyltransferase family (OTC)
Family:
Ornithine/aspartate carbamoyltransferase family (OTC)PANTHER:PTHR45753
Representative Members: OTC (human, mitochondrial)UniProtKB:P00480

Function

ornithine carbamoyltransferase activityGO:0004585
Substrates: carbamoyl phosphate L-ornithine
Products: L-citrulline phosphate

Locations

mitochondrial matrixGO:0005759

Transfers the carbamoyl group of carbamoyl phosphate to the delta-amino group of L-ornithine, producing L-citrulline. The X-linked human enzyme (OTC/OTCD) is the most common urea cycle disorder. The PANTHER family is homologous to the aspartate carbamoyltransferases (bacterial argF/argI ornithine carbamoyltransferases are orthologs), reflecting a shared carbamoyltransferase fold.

Part 4: mitochondrial ornithine/citrulline exchange
citrulline export / ornithine import across the inner membrane (SLC25A15)Transport Stepornithine_citrulline_transport

Annotons

SLC25A15/ORNT1: ornithine/citrulline antiporter
slc25a15_activity
Participant: Family: Mitochondrial basic-amino-acid (ornithine) carrier family (SLC25A15/SLC25A2)
Family:
Mitochondrial basic-amino-acid (ornithine) carrier family (SLC25A15/SLC25A2)PANTHER:PTHR45624
Representative Members: SLC25A15 / ORNT1 (human)UniProtKB:Q9Y619 SLC25A2 / ORNT2 (human paralog)UniProtKB:Q9BXI2

Function

L-ornithine transmembrane transporter activityGO:0000064
Substrates: L-citrulline (matrix) L-ornithine (cytosol)
Products: L-citrulline (cytosol) L-ornithine (matrix)

Locations

mitochondrial inner membraneGO:0005743

Couples the mitochondrial and cytosolic halves of the cycle: exports OTC-made citrulline to the cytosol in exchange for the ornithine regenerated by ARG1, so ornithine is recycled. Loss of SLC25A15 causes HHH syndrome (hyperornithinemia-hyperammonemia- homocitrullinuria). The paralog SLC25A2/ORNT2 partially overlaps in specificity.

Part 5: cytosolic condensation of citrulline with aspartate
L-citrulline + L-aspartate + ATP to argininosuccinate + AMP + PPiReactionass1_step

Annotons

ASS1: argininosuccinate synthase
ass1_activity
Participant: Family: Argininosuccinate synthase family (ASS1)
Family:
Argininosuccinate synthase family (ASS1)PANTHER:PTHR11587
Representative Members: ASS1 (human)UniProtKB:P00966

Function

argininosuccinate synthase activityGO:0004055
Substrates: L-citrulline L-aspartate ATP
Products: N(omega)-(L-arginino)succinate AMP diphosphate

Locations

cytosolGO:0005829

Rate-limiting cytosolic step: condenses citrulline with aspartate (the second nitrogen donor) using ATP (cleaved to AMP + PPi) to form argininosuccinate. Deficiency causes citrullinemia type I.

Part 6: cleavage to arginine and fumarate
argininosuccinate to L-arginine + fumarateReactionasl_step

Annotons

ASL: argininosuccinate lyase
asl_activity
Participant: Family: Argininosuccinate lyase / fumarase superfamily (ASL)
Family:
Argininosuccinate lyase / fumarase superfamily (ASL)PANTHER:PTHR43814
Representative Members: ASL (human)UniProtKB:P04424

Function

argininosuccinate lyase activityGO:0004056
Substrates: N(omega)-(L-arginino)succinate
Products: L-arginine fumarate

Locations

cytosolGO:0005829

Cleaves argininosuccinate into L-arginine and fumarate; the fumarate feeds the TCA cycle and regenerates aspartate (the aspartate-argininosuccinate shunt). ASL is also required for channeling arginine to nitric-oxide synthase, so ASL deficiency (argininosuccinic aciduria) has systemic features beyond hyperammonemia. Member of the lyase/fumarase (aspartase) superfamily.

Part 7: terminal hydrolysis to urea, regenerating ornithine
L-arginine + H2O to L-ornithine + ureaReactionarg1_step

Annotons

ARG1: arginase 1
arg1_activity
Participant: Family: Arginase / ureohydrolase family (ARG1/ARG2)
Family:
Arginase / ureohydrolase family (ARG1/ARG2)PANTHER:PTHR43782
Representative Members: ARG1 (human, cytosolic, hepatic)UniProtKB:P05089 ARG2 (human, mitochondrial paralog)UniProtKB:P78540

Function

arginase activityGO:0004053
Substrates: L-arginine water
Products: L-ornithine urea

Locations

cytosolGO:0005829

Terminal step: hydrolyses arginine to urea (the excreted product) and ornithine, which is re-imported to mitochondria to close the cycle. ARG1 is the cytosolic hepatic isoform whose deficiency causes arginase deficiency (argininemia, spastic diplegia); the manganese metalloenzyme paralog ARG2 is mitochondrial and extrahepatic and does not substitute for hepatic ureagenesis.

Part 8: cytosolic aspartate supply (aspartate/glutamate carrier)
mitochondrial aspartate export for the ASS1 step (SLC25A13, citrin)Transport Stepcitrin_aspartate_supply

Annotons

SLC25A13/citrin: aspartate/glutamate antiporter
slc25a13_activity
Participant: Family: Mitochondrial aspartate/glutamate carrier family (SLC25A13/SLC25A12)
Family:
Mitochondrial aspartate/glutamate carrier family (SLC25A13/SLC25A12)PANTHER:PTHR45678
Representative Members: SLC25A13 / citrin (human, liver)UniProtKB:Q9UJS0 SLC25A12 / aralar (human paralog)UniProtKB:O75746

Function

L-aspartate transmembrane transporter activityGO:0015183
Substrates: L-aspartate (matrix) L-glutamate (cytosol)
Products: L-aspartate (cytosol) L-glutamate (matrix)

Locations

mitochondrial inner membraneGO:0005743

Ancillary but essential: the liver-type aspartate/glutamate carrier citrin exports mitochondrial aspartate to the cytosol, supplying the second nitrogen donor consumed by ASS1 and completing the malate-aspartate / aspartate-argininosuccinate shunt. Citrin deficiency causes citrullinemia type II (CTLN2) and NICCD. The paralog SLC25A12/aralar performs the same exchange in brain/muscle.