PHYKPL

Summary

PHYKPL (5-phosphohydroxy-L-lysine phospho-lyase, HGNC:28249) is a protein-coding gene on chromosome 5q35.3, encoding 5-phosphohydroxy-L-lysine phospho-lyase (Q8IUZ5). Catalyzes the pyridoxal-phosphate-dependent breakdown of 5-phosphohydroxy-L-lysine, converting it to ammonia, inorganic phosphate and 2-aminoadipate semialdehyde.

This is a nuclear gene encoding a mitochondrial enzyme that catalyzes the conversion of 5-phosphonooxy-L-lysine to ammonia, inorganic phosphate, and 2-aminoadipate semialdehyde. Mutations in this gene may cause phosphohydroxylysinuria. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 85007 — RefSeq curated summary.

At a glance

• Gene–disease (curated): phosphohydroxylysinuria (Limited, ClinGen)
• Clinical variants (ClinVar): 118 total
• Phenotypes (HPO): 3
• Druggable target: yes
• MANE Select transcript: NM_153373

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28249
Approved symbol	PHYKPL
Name	5-phosphohydroxy-L-lysine phospho-lyase
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC15875
Ensembl gene	ENSG00000175309
Ensembl biotype	protein_coding
OMIM	614683
Entrez	85007

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 33 protein_coding, 9 retained_intron, 5 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000308158, ENST00000323594, ENST00000393488, ENST00000474052, ENST00000476170, ENST00000476487, ENST00000481436, ENST00000481811, ENST00000489262, ENST00000493197, ENST00000494126, ENST00000504096, ENST00000506001, ENST00000506045, ENST00000510913, ENST00000510991, ENST00000511716, ENST00000514424, ENST00000850854, ENST00000884991, ENST00000884993, ENST00000884994, ENST00000884995, ENST00000884996, ENST00000884998, ENST00000885000, ENST00000885002, ENST00000885004, ENST00000885005, ENST00000885007, ENST00000885009, ENST00000885010, ENST00000885011, ENST00000885012, ENST00000885013, ENST00000885014, ENST00000885015, ENST00000916242, ENST00000916243, ENST00000916244, ENST00000962523, ENST00000962524, ENST00000962525, ENST00000962526, ENST00000962527, ENST00000962528, ENST00000962529, ENST00000962530, ENST00000962531

RefSeq mRNA: 2 — MANE Select: NM_153373 NM_001278346, NM_153373

CCDS: CCDS4434

Canonical transcript exons

ENST00000308158 — 13 exons

Exon	Start	End
ENSE00001778171	178224448	178224564
ENSE00001820392	178232492	178232802
ENSE00001929179	178208471	178208915
ENSE00003562527	178224642	178224729
ENSE00003575676	178229940	178230099
ENSE00003646616	178225355	178225429
ENSE00003653543	178231405	178231523
ENSE00004282507	178211890	178211970
ENSE00004282509	178212973	178213103
ENSE00004282510	178222355	178222580
ENSE00004282512	178215276	178215430
ENSE00004282514	178222852	178222934
ENSE00004282515	178214796	178214885

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.6024 / max 490.8687, expressed in 1813 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65163	13.6163	1775
65161	3.9382	1628
65160	3.4497	1457
65158	0.4195	186
65159	0.0876	26
65157	0.0531	15
65162	0.0380	7

Top tissues by expression

259 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	99.03	gold quality
right lobe of thyroid gland	UBERON:0001119	98.47	gold quality
right uterine tube	UBERON:0001302	98.31	gold quality
left lobe of thyroid gland	UBERON:0001120	98.19	gold quality
granulocyte	CL:0000094	98.17	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.07	gold quality
right ovary	UBERON:0002118	97.94	gold quality
endocervix	UBERON:0000458	97.88	gold quality
transverse colon	UBERON:0001157	97.80	gold quality
left ovary	UBERON:0002119	97.76	gold quality
right lobe of liver	UBERON:0001114	97.63	gold quality
thyroid gland	UBERON:0002046	97.56	gold quality
right testis	UBERON:0004534	97.52	gold quality
body of uterus	UBERON:0009853	97.47	gold quality
left testis	UBERON:0004533	97.46	gold quality
rectum	UBERON:0001052	97.35	gold quality
mucosa of transverse colon	UBERON:0004991	97.32	gold quality
spleen	UBERON:0002106	97.29	gold quality
metanephros cortex	UBERON:0010533	97.27	gold quality
mucosa of stomach	UBERON:0001199	97.26	gold quality
tibial nerve	UBERON:0001323	97.23	gold quality
left uterine tube	UBERON:0001303	97.18	gold quality
small intestine	UBERON:0002108	97.05	gold quality
omental fat pad	UBERON:0010414	97.04	gold quality
peritoneum	UBERON:0002358	97.00	gold quality
vermiform appendix	UBERON:0001154	96.95	gold quality
body of stomach	UBERON:0001161	96.86	gold quality
body of pancreas	UBERON:0001150	96.78	gold quality
ileal mucosa	UBERON:0000331	96.77	gold quality
apex of heart	UBERON:0002098	96.65	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	12.43
E-ANND-3	yes	6.14
E-MTAB-6678	yes	5.90

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Phosphohydroxylysinuria is due to mutations in the AGXT2L2 gene and the resulting lack of activity of phosphohydroxylysine phospholyase in vivo. (PMID:23242558)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	phykpl	ENSDARG00000040566
mus_musculus	Phykpl	ENSMUSG00000020359
rattus_norvegicus	Phykpl	ENSRNOG00000047933

Paralogs (4): OAT (ENSG00000065154), AGXT2 (ENSG00000113492), ETNPPL (ENSG00000164089), ABAT (ENSG00000183044)

Protein

Protein identifiers

5-phosphohydroxy-L-lysine phospho-lyase — Q8IUZ5 (reviewed: Q8IUZ5)

Alternative names: Alanine–glyoxylate aminotransferase 2-like 2

All UniProt accessions (8): D6RAR0, D6RCB8, D6RD89, Q8IUZ5, H0Y9N3, H0YAK5, H7BXR0, H7BYK2

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the pyridoxal-phosphate-dependent breakdown of 5-phosphohydroxy-L-lysine, converting it to ammonia, inorganic phosphate and 2-aminoadipate semialdehyde.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion.

Disease relevance. Phosphohydroxylysinuria (PHLU) [MIM:615011] A condition characterized by elevated phosphohydroxylysine in the urine. There is no clinical phenotype associated with this finding other than the urinary metabolites. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IUZ5-1	1	yes
Q8IUZ5-2	2
Q8IUZ5-3	3

RefSeq proteins (2): NP_001265275, NP_699204* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005814	Aminotrans_3	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR049704	Aminotrans_3_PPA_site	Conserved_site

Pfam: PF00202

Enzyme classification (BRENDA):

• EC 4.2.3.134 — 5-phosphooxy-L-lysine phospho-lyase (BRENDA: 3 organisms, 2 substrates, 2 inhibitors, 3 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(5R)-5-PHOSPHOHYDROXY-L-LYSINE	0.0036–0.0169	3

Catalyzed reactions (Rhea), 1 shown:

• (5R)-5-phosphooxy-L-lysine + H2O = (S)-2-amino-6-oxohexanoate + NH4(+) + phosphate (RHEA:34091)

UniProt features (7 total): sequence variant 3, splice variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUZ5-F1	96.20	0.95

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 278

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1442490	Collagen degradation
R-HSA-71064	Lysine catabolism
R-HSA-1430728	Metabolism
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1474244	Extracellular matrix organization
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 0 (showing top):

GO Biological Process (0):

GO Molecular Function (5): transaminase activity (GO:0008483), lyase activity (GO:0016829), pyridoxal phosphate binding (GO:0030170), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (2): mitochondrial matrix (GO:0005759), mitochondrion (GO:0005739)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Degradation of the extracellular matrix	1
Metabolism of amino acids and derivatives	1
Extracellular matrix organization	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transferase activity, transferring nitrogenous groups	1
catalytic activity	1
anion binding	1
vitamin B6 binding	1
protein binding	1
binding	1
mitochondrion	1
intracellular organelle lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1169 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHYKPL	DERA	Q9Y315	512
PHYKPL	HYKK	A2RU49	494
PHYKPL	SPG21	Q9NZD8	488
PHYKPL	INPP5K	Q9BT40	474
PHYKPL	KDSR	Q06136	457
PHYKPL	GLDC	P23378	438
PHYKPL	DGKQ	P52824	429
PHYKPL	ZNF575	Q86XF7	419
PHYKPL	HDHD2	Q9H0R4	411
PHYKPL	AASDH	Q4L235	408
PHYKPL	RMND5B	Q96G75	405
PHYKPL	COL23A1	Q86Y22	404
PHYKPL	C5orf15	Q8NC54	400
PHYKPL	RNF121	Q9H920	396
PHYKPL	AADAT	Q8N5Z0	382

IntAct

26 interactions, top by confidence:

A	B	Type	Score
PHYKPL	PHYKPL	psi-mi:“MI:0915”(physical association)	0.800
VAC14	PHYKPL	psi-mi:“MI:0915”(physical association)	0.670
PHYKPL	VAC14	psi-mi:“MI:0915”(physical association)	0.670
USO1	PHYKPL	psi-mi:“MI:0915”(physical association)	0.560
PHYKPL	USO1	psi-mi:“MI:0915”(physical association)	0.560
PHYKPL	LNX2	psi-mi:“MI:0915”(physical association)	0.550
LNX2	PHYKPL	psi-mi:“MI:0915”(physical association)	0.550
POT1	PHYKPL	psi-mi:“MI:0915”(physical association)	0.510
PHYKPL	GIT1	psi-mi:“MI:0915”(physical association)	0.400
Cep131	WBP2	psi-mi:“MI:0914”(association)	0.350
ZNF684	GAPDHS	psi-mi:“MI:0914”(association)	0.350
BFAR	PHYKPL	psi-mi:“MI:0914”(association)	0.350
METTL17	PHYKPL	psi-mi:“MI:0914”(association)	0.350
POT1	PHYKPL	psi-mi:“MI:0915”(physical association)	0.000
PHYKPL	PHYKPL	psi-mi:“MI:0915”(physical association)	0.000
	PHYKPL	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): PHYKPL (Two-hybrid), PHYKPL (Two-hybrid), PHYKPL (Two-hybrid), PHYKPL (Two-hybrid), PHYKPL (Two-hybrid), PHYKPL (Affinity Capture-MS), PHYKPL (Affinity Capture-MS), PHYKPL (Affinity Capture-RNA), PHYKPL (Two-hybrid), PHYKPL (Two-hybrid), PHYKPL (Two-hybrid), PHYKPL (Affinity Capture-RNA), PHYKPL (Affinity Capture-RNA), PHYKPL (Affinity Capture-MS), PHYKPL (Affinity Capture-MS)

ESM2 similar proteins: A0A098DDI1, B8BBZ7, D6R3B6, E1AQY3, E1V7V7, E5Y945, O13837, O74548, O82521, O94562, P17649, P18492, P28269, P31593, P42799, P44951, P45621, P49604, P91408, Q01K11, Q01K12, Q21217, Q39566, Q40147, Q42522, Q53196, Q54KM6, Q55FI1, Q6C846, Q6CJ86, Q6YZE2, Q6ZCF0, Q6ZH29, Q7SY54, Q7XN11, Q7XN12, Q84P52, Q84P53, Q84P54, Q85WB7

Diamond homologs: A0A098DDI1, A0QYS9, A1ASE9, A1BJG8, A3CU65, A4XC73, A5FIM3, A5UML0, A6T4V8, A8M6S5, B0B9W0, B0BBJ0, B0TFV0, B1I4L1, B2VE25, B3DY05, B3QSA6, B4SGW1, B5F846, B5Y1L5, C1F911, H3ZR39, M1GRN3, O27392, O50131, O57878, O84212, P22256, P30268, P33189, P40829, P50457, P63505, P91408, P94427, P9WQ78, P9WQ79, Q0AAH7, Q17QF0, Q2JFQ1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

118 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	13
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2983 predictions. Top by Δscore:

Variant	Effect	Δscore
5:178207221:GCAAG:G	donor_gain	1.0000
5:178207225:GGTA:G	donor_loss	1.0000
5:178207226:G:A	donor_loss	1.0000
5:178207226:G:GG	donor_gain	1.0000
5:178207227:T:G	donor_loss	1.0000
5:178209326:TTAGT:T	acceptor_loss	1.0000
5:178209327:TAG:T	acceptor_loss	1.0000
5:178209328:A:AG	acceptor_gain	1.0000
5:178209328:A:C	acceptor_loss	1.0000
5:178209328:AGT:A	acceptor_gain	1.0000
5:178209328:AGTGT:A	acceptor_gain	1.0000
5:178209329:G:GA	acceptor_gain	1.0000
5:178209329:GT:G	acceptor_gain	1.0000
5:178209329:GTG:G	acceptor_gain	1.0000
5:178209329:GTGT:G	acceptor_gain	1.0000
5:178209329:GTGTG:G	acceptor_gain	1.0000
5:178209448:GT:G	donor_loss	1.0000
5:178210129:CA:C	acceptor_loss	1.0000
5:178210130:A:AG	acceptor_gain	1.0000
5:178210130:AGGTC:A	acceptor_loss	1.0000
5:178210131:G:GA	acceptor_gain	1.0000
5:178210131:GGT:G	acceptor_gain	1.0000
5:178210131:GGTC:G	acceptor_gain	1.0000
5:178210131:GGTCA:G	acceptor_gain	1.0000
5:178210268:CTACA:C	donor_gain	1.0000
5:178210269:TACA:T	donor_gain	1.0000
5:178210270:ACA:A	donor_gain	1.0000
5:178210271:CA:C	donor_gain	1.0000
5:178210273:GT:G	donor_loss	1.0000
5:178210273:GTAA:G	donor_gain	1.0000

AlphaMissense

2965 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:178224690:A:C	S151R	0.998
5:178224690:A:T	S151R	0.998
5:178224692:T:G	S151R	0.998
5:178222361:G:C	F307L	0.995
5:178222361:G:T	F307L	0.995
5:178222363:A:G	F307L	0.995
5:178222902:A:C	S217R	0.994
5:178222902:A:T	S217R	0.994
5:178222904:T:G	S217R	0.994
5:178224725:A:G	Y140H	0.994
5:178225412:A:G	L119P	0.994
5:178232507:C:A	R15M	0.994
5:178222461:A:T	V274D	0.993
5:178222542:T:A	E247V	0.993
5:178224718:C:A	G142V	0.993
5:178225409:G:T	A120D	0.993
5:178222504:A:G	W260R	0.992
5:178222504:A:T	W260R	0.992
5:178222546:C:G	D246H	0.992
5:178222551:A:T	V244D	0.992
5:178224718:C:T	G142D	0.992
5:178224722:G:C	H141D	0.992
5:178229944:A:G	S112P	0.992
5:178231426:A:G	C53R	0.992
5:178215419:G:C	S313R	0.991
5:178215419:G:T	S313R	0.991
5:178215421:T:G	S313R	0.991
5:178222545:T:A	D246V	0.991
5:178225397:G:T	A124D	0.991
5:178229943:G:A	S112F	0.991

dbSNP variants (sampled 300 via entrez): RS1000002225 (5:178214545 G>T), RS1000008202 (5:178221701 C>T), RS1000290605 (5:178230282 G>A,T), RS1000294138 (5:178210965 T>C), RS1000389512 (5:178234478 C>G), RS1000420644 (5:178234244 G>T), RS1000505586 (5:178221463 C>G), RS1000559336 (5:178210000 G>A,C), RS1000577555 (5:178231251 C>T), RS1000620055 (5:178232453 AGCCCCGCGCCCCCC>A), RS1000868319 (5:178221441 G>A), RS1000899703 (5:178211555 G>T), RS1000975094 (5:178216922 G>A), RS1001051934 (5:178217550 G>A,C,T), RS1001061841 (5:178226356 C>T)

Disease associations

OMIM: gene MIM:614683 | disease phenotypes: MIM:615011

GenCC curated gene-disease

Disease	Classification	Inheritance
phosphohydroxylysinuria	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
phosphohydroxylysinuria	Limited	AR

Mondo (1): phosphohydroxylysinuria (MONDO:0014008)

Orphanet (0):

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0031870	Phosphohydroxylysinuria
HP:6000806	Elevated urinary phosphohydroxylysine level

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066352 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
sodium arsenite	affects expression, decreases expression, increases abundance, increases expression	4
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	decreases expression, increases abundance	1
Vehicle Emissions	decreases expression, decreases reaction	1
Calcitriol	increases expression, affects cotreatment	1
Coumestrol	decreases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Tretinoin	increases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652043	Binding	Binding affinity to human PHYKPL incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.