LYS4

UniProt ID: P49367
Organism: Saccharomyces cerevisiae S288C
Review Status: DRAFT
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Gene Description

Mitochondrial homoaconitase (homoaconitate hydratase, EC 4.2.1.36) of Saccharomyces cerevisiae, a member of the aconitase/isopropylmalate isomerase family with a [4Fe-4S] cluster. Lys4 catalyses the reversible hydration of cis-homoaconitate to (2R,3S)-homoisocitrate in the alpha-aminoadipate pathway of lysine biosynthesis. Purified Lys4 does not act on homocitrate; the preceding dehydration of homocitrate to cis-homoaconitate is carried out by the mitochondrial aconitase paralog Aco2, which in yeast contributes specifically to lysine biosynthesis, so the homocitrate-to-homoisocitrate isomerisation needs two aconitase-family enzymes. Lys4 is in mitochondria, with the downstream homoisocitrate dehydrogenase Lys12, and lys4 mutants are lysine auxotrophs.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004409 homoaconitate hydratase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined IEA (InterPro/Rhea:15485/EC 4.2.1.36). GO:0004409 is defined by the (2R,3S)-homoisocitrate = cis-homoaconitate + H2O reaction, which is exactly the half-reaction that purified yeast Lys4 catalyses; it does not dehydrate homocitrate (that step is performed by Aco2).
Supporting Evidence:
PMID:23106124
Although we confirmed an essential contribution of homoaconitases from Saccharomyces cerevisiae and Aspergillus fumigatus, these enzymes only catalysed the interconversion between homoaconitate and homoisocitrate.
file:yeast/LYS4/LYS4-uniprot.txt
FUNCTION: Catalyzes the reversible hydration of cis-homoaconitate to
GO:0004409 homoaconitate hydratase activity
ISA
PMID:9268014
The Aspergillus nidulans lysF gene encodes homoaconitase, an... 		ACCEPT
Summary: Sequence alignment to the characterised Aspergillus nidulans LysF homoaconitase (Q92412), which shares 55% identity with yeast Lys4 including the Fe-S cluster cysteines. Supported independently by direct assays of yeast Lys4 (Fazius et al. 2012).
Supporting Evidence:
PMID:9268014
Computer analysis revealed 55% amino acid sequence identity between the products of the putative homoaconitase ORF of A. nidulans and that of the recently sequenced homologous Saccharomyces cerevisiae.
PMID:23106124
Although we confirmed an essential contribution of homoaconitases from Saccharomyces cerevisiae and Aspergillus fumigatus, these enzymes only catalysed the interconversion between homoaconitate and homoisocitrate.
GO:0004409 homoaconitate hydratase activity
RCA
GO_REF:0000123 		ACCEPT
Summary: YeastPathways assigns the cis-homoaconitate -> homoisocitrate hydration to Lys4. Correct. Note that the preceding homocitrate -> cis-homoaconitate dehydration is catalysed by the aconitase paralog Aco2, not by Lys4.
Supporting Evidence:
PMID:23106124
Although we confirmed an essential contribution of homoaconitases from Saccharomyces cerevisiae and Aspergillus fumigatus, these enzymes only catalysed the interconversion between homoaconitate and homoisocitrate.
PMID:23106124
Aco2p specifically and exclusively contributes to lysine biosynthesis
GO:0005515 protein binding
IPI
PMID:16606443
Comparative analysis of Saccharomyces cerevisiae WW domains ... 		REMOVE
Summary: Lys4 bound Rsp5 WW domains (with/from P39940) in a protein-microarray screen of yeast WW-domain interactors. This may reflect recognition by the Rsp5 ubiquitin ligase, but 'protein binding' conveys no information about Lys4 function and no consequence has been shown. Removal reflects the uninformative term, not doubt about the interaction.
Supporting Evidence:
PMID:16606443
We used protein microarray technology to generate a protein interaction map for 12 of the 13 WW domains present in proteins of the yeast S. cerevisiae.
GO:0005739 mitochondrion
HDA
PMID:14562095
Global analysis of protein localization in budding yeast. 		ACCEPT
Summary: Genome-wide GFP-fusion localisation (Huh et al. 2003) placed Lys4 in mitochondria; UniProt uses this as the experimental basis of its location.
Supporting Evidence:
PMID:14562095
We classify these proteins, representing 75% of the yeast proteome, into 22 distinct subcellular localization categories
file:yeast/LYS4/LYS4-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:14562095}.
GO:0005739 mitochondrion
HDA
PMID:14576278
The proteome of Saccharomyces cerevisiae mitochondria. 		ACCEPT
Summary: Lys4 detected in the proteome of highly purified mitochondria. Consistent with GFP localisation.
Supporting Evidence:
PMID:14576278
The proteins of highly pure yeast mitochondria were separated by several independent methods and analyzed by tandem MS.
GO:0005739 mitochondrion
HDA
PMID:16823961
Toward the complete yeast mitochondrial proteome: multidimen... 		ACCEPT
Summary: Lys4 detected in the PROMITO mitochondrial proteome. Consistent with GFP localisation.
Supporting Evidence:
PMID:16823961
A total of 851 different proteins (PROMITO dataset) were identified by use of multidimensional LC-MS/MS
GO:0005739 mitochondrion
HDA
PMID:24769239
Quantitative variations of the mitochondrial proteome and ph... 		ACCEPT
Summary: Lys4 quantified in isolated mitochondria from fermentative and respiratory cultures. Consistent with its mitochondrial location.
Supporting Evidence:
PMID:24769239
we performed an overall quantitative proteomic and phosphoproteomic study of isolated mitochondria extracted from yeast grown on fermentative (glucose or galactose) and respiratory (lactate) media
GO:0005739 mitochondrion
IEA
GO_REF:0000044 		ACCEPT
Summary: UniProt subcellular location (Mitochondrion) mapped to GO. Correct.
Supporting Evidence:
file:yeast/LYS4/LYS4-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:14562095}.
GO:0005829 cytosol
RCA
GO_REF:0000123 		MODIFY
Summary: RCA default location from the YeastPathways LYSINE-AMINOAD-PWY-2 diagram. Lys4 is a mitochondrial Fe-S enzyme (GFP localisation and several mitochondrial proteomes), and its partner Aco2 is also mitochondrial; there is no evidence for cytosolic activity. Replace with mitochondrion.
Proposed replacements: mitochondrion
Supporting Evidence:
file:yeast/LYS4/LYS4-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:14562095}.
GO:0009085 L-lysine biosynthetic process
IEA
GO_REF:0000120 		ACCEPT
Summary: InterPro/UniPathway mapping to lysine biosynthesis (step 3/5). Correct.
Supporting Evidence:
file:yeast/LYS4/LYS4-uniprot.txt
pathway; L-alpha-aminoadipate from 2-oxoglutarate: step 3/5.
GO:0009085 L-lysine biosynthetic process
IMP
PMID:2507177
Cloning and physical characterization of linked lysine genes... 		ACCEPT
Summary: The cloned LYS4 locus complemented lys4 lysine auxotrophs; lys4 mutants require lysine. Fazius et al. also confirmed the essential contribution of Lys4 to lysine synthesis.
Supporting Evidence:
PMID:2507177
complemented simultaneously MO-59-13c lys4, LU75 lys15 and LU32 lys4lys15 (double) mutations of Saccharomyces cerevisiae
PMID:23106124
Although we confirmed an essential contribution of homoaconitases from Saccharomyces cerevisiae and Aspergillus fumigatus, these enzymes only catalysed the interconversion between homoaconitate and homoisocitrate.
GO:0009085 L-lysine biosynthetic process
RCA
GO_REF:0000123 		ACCEPT
Summary: YeastPathways LYSINE-AMINOAD-PWY-2; Lys4 catalyses the homoaconitate hydration step. Correct.
Supporting Evidence:
PMID:23106124
Although we confirmed an essential contribution of homoaconitases from Saccharomyces cerevisiae and Aspergillus fumigatus, these enzymes only catalysed the interconversion between homoaconitate and homoisocitrate.
GO:0051539 4 iron, 4 sulfur cluster binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro (aconitase family) mapping to 4Fe-4S cluster binding. Lys4 retains the aconitase-family cluster-ligating cysteines and UniProt records one [4Fe-4S] cluster per subunit by similarity. Correct cofactor property, not the core function.
Supporting Evidence:
PMID:9268014
The similarity was particularly obvious in a region of cysteine residues, which are characteristic of an iron-sulfur cluster, implying that homoaconitase contains such a cluster.

Core Functions

Hydration of cis-homoaconitate to homoisocitrate (EC 4.2.1.36) in the mitochondrial part of the lysine biosynthesis pathway; Fe-S-cluster dependent. The upstream homocitrate dehydration is done by Aco2, not Lys4.

Molecular Function:
homoaconitate hydratase activity
Directly Involved In:
L-lysine biosynthetic process
Cellular Locations:
mitochondrion
Supporting Evidence:
  • PMID:23106124
    Although we confirmed an essential contribution of homoaconitases from Saccharomyces cerevisiae and Aspergillus fumigatus, these enzymes only catalysed the interconversion between homoaconitate and homoisocitrate.
  • file:yeast/LYS4/LYS4-uniprot.txt
    FUNCTION: Catalyzes the reversible hydration of cis-homoaconitate to
  • file:yeast/LYS4/LYS4-uniprot.txt
    SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:14562095}.

References

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Deep Research

SGD

(LYS4-deep-research-sgd.md)
SGD gene description for LYS4 (yeast) SGD

SGD gene description for LYS4 (yeast)

Homoaconitase; catalyzes the conversion of homocitrate to homoisocitrate, which is a step in the lysine biosynthesis pathway

📚 Additional Documentation

Notes

(LYS4-notes.md)

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