L3HYPDH

Summary

L3HYPDH (trans-L-3-hydroxyproline dehydratase, HGNC:20488) is a protein-coding gene on chromosome 14q23.1, encoding Trans-3-hydroxy-L-proline dehydratase (Q96EM0). Catalyzes the dehydration of trans-3-hydroxy-L-proline to Delta(1)-pyrroline-2-carboxylate (Pyr2C).

The protein encoded by this gene is a dehydratase that converts trans-3-hydroxy-L-proline to delta(1)-pyrroline-2-carboxylate. This enzyme may function to degrade dietary proteins that contain trans-3-hydroxy-L-proline as well as other proteins such as collagen IV. The encoded protein can be converted to an epimerase by changing a threonine to a cysteine at a catalytic site.

Source: NCBI Gene 112849 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 80 total
• MANE Select transcript: NM_144581

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20488
Approved symbol	L3HYPDH
Name	trans-L-3-hydroxyproline dehydratase
Location	14q23.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25436
Ensembl gene	ENSG00000126790
Ensembl biotype	protein_coding
OMIM	614811
Entrez	112849

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000247194, ENST00000463432, ENST00000466522, ENST00000478430, ENST00000481608, ENST00000487285, ENST00000527981, ENST00000532049, ENST00000543619, ENST00000887796

RefSeq mRNA: 4 — MANE Select: NM_144581 NM_001331158, NM_001331159, NM_001331164, NM_144581

CCDS: CCDS9739

Canonical transcript exons

ENST00000247194 — 5 exons

Exon	Start	End
ENSE00001144973	59476092	59476214
ENSE00001308219	59472606	59473090
ENSE00002087055	59483809	59484408
ENSE00003610512	59479182	59479351
ENSE00003789469	59475869	59476006

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 96.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.0892 / max 217.0966, expressed in 1767 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143450	9.4353	1722
143451	2.8647	1479
143448	2.6124	972
143447	0.4769	282
143445	0.3600	137
143449	0.3398	184

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.69	gold quality
right coronary artery	UBERON:0001625	95.77	gold quality
right testis	UBERON:0004534	94.92	gold quality
left coronary artery	UBERON:0001626	94.48	gold quality
right ovary	UBERON:0002118	94.35	gold quality
left testis	UBERON:0004533	94.35	gold quality
left ovary	UBERON:0002119	94.29	gold quality
stromal cell of endometrium	CL:0002255	93.97	gold quality
body of pancreas	UBERON:0001150	93.70	gold quality
ascending aorta	UBERON:0001496	93.56	gold quality
right lobe of thyroid gland	UBERON:0001119	93.45	gold quality
left lobe of thyroid gland	UBERON:0001120	93.42	gold quality
left uterine tube	UBERON:0001303	93.42	gold quality
thoracic aorta	UBERON:0001515	93.42	gold quality
body of uterus	UBERON:0009853	93.39	gold quality
popliteal artery	UBERON:0002250	93.38	gold quality
tibial artery	UBERON:0007610	93.38	gold quality
aorta	UBERON:0000947	93.26	gold quality
adenohypophysis	UBERON:0002196	93.16	gold quality
coronary artery	UBERON:0001621	93.13	gold quality
endocervix	UBERON:0000458	92.99	gold quality
metanephros cortex	UBERON:0010533	92.79	gold quality
ectocervix	UBERON:0012249	92.48	gold quality
minor salivary gland	UBERON:0001830	92.47	gold quality
gall bladder	UBERON:0002110	92.34	gold quality
tibial nerve	UBERON:0001323	92.21	gold quality
descending thoracic aorta	UBERON:0002345	92.18	gold quality
testis	UBERON:0000473	92.16	gold quality
omental fat pad	UBERON:0010414	92.14	gold quality
right adrenal gland cortex	UBERON:0035827	92.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

43 targeting L3HYPDH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-3146	98.85	66.77	601
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-606	98.72	67.34	960
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-4712-3P	98.52	65.39	822
HSA-MIR-3689A-5P	98.35	70.12	1049

Literature-anchored findings (GeneRIF, showing 1)

• human trans-3-hydroxy-L-proline dehydratase is the first characterized member of a novel family of proline racemase-like enzymes (PMID:22528483)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio	l3hypdh	ENSDARG00000103763
mus_musculus	L3hypdh	ENSMUSG00000019718

Protein

Protein identifiers

Trans-3-hydroxy-L-proline dehydratase — Q96EM0 (reviewed: Q96EM0)

Alternative names: Trans-L-3-hydroxyproline dehydratase

All UniProt accessions (3): Q96EM0, D6RC46, E9PKK7

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the dehydration of trans-3-hydroxy-L-proline to Delta(1)-pyrroline-2-carboxylate (Pyr2C). May be required to degrade trans-3-hydroxy-L-proline from the diet and originating from the degradation of proteins such as collagen-IV that contain it.

Subunit / interactions. Homodimer.

Tissue specificity. Ubiquitously expressed.

Miscellaneous. In contrast to the T.cruzi proline racemase enzyme, lacks the conserved Cys at position 273 which is replaced by a Thr residue, transforming the racemase activity into dehydratase activity.

Similarity. Belongs to the proline racemase family.

RefSeq proteins (4): NP_001318087, NP_001318088, NP_001318093, NP_653182* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008794	Pro_racemase_fam	Family

Pfam: PF05544

Enzyme classification (BRENDA):

• EC 4.2.1.77 — trans-L-3-hydroxyproline dehydratase (BRENDA: 6 organisms, 4 substrates, 0 inhibitors, 8 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRANS-3-HYDROXY-L-PROLINE	0.0029–14.3	7
TRANS-L-3-HYDROXYPROLINE	6.67	1

Catalyzed reactions (Rhea), 1 shown:

• trans-3-hydroxy-L-proline = 1-pyrroline-2-carboxylate + H2O (RHEA:10320)

UniProt features (39 total): strand 16, helix 6, turn 6, sequence variant 4, binding site 3, chain 1, active site 1, sequence conflict 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7QPO	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96EM0-F1	96.05	0.96

Functional residue map

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

Catalytic / active sites (1): 104 (proton acceptor)

Ligand- & substrate-binding residues (3): 105–106; 269; 274–275

Mutagenesis-validated functional residues (1):

Position	Phenotype
273	regains racemase activity, catalyzing the conversion of trans-3-hydroxy-l-proline to cis-3-hydroxy-d-proline. also catal

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 77 (showing top): WEI_MYCN_TARGETS_WITH_E_BOX, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, chr14q23, GOMF_HYDRO_LYASE_ACTIVITY, GOMF_RACEMASE_AND_EPIMERASE_ACTIVITY, GOMF_ISOMERASE_ACTIVITY, KRIGE_RESPONSE_TO_TOSEDOSTAT_6HR_DN, PANGAS_TUMOR_SUPPRESSION_BY_SMAD1_AND_SMAD5_UP, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_B, BRUINS_UVC_RESPONSE_MIDDLE, LIM_MAMMARY_STEM_CELL_UP, IRF1_01, NFE2L2.V2, FEV_TARGET_GENES, FOXD2_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (3): hydro-lyase activity (GO:0016836), trans-L-3-hydroxyproline dehydratase activity (GO:0050346), lyase activity (GO:0016829)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carbon-oxygen lyase activity	1
hydro-lyase activity	1
catalytic activity	1

Protein interactions and networks

STRING

408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
L3HYPDH	JKAMP	Q9P055	570
L3HYPDH	CRYM	Q14894	545
L3HYPDH	PYCR3	Q53H96	528
L3HYPDH	KCTD18	Q6PI47	477
L3HYPDH	RNF122	Q9H9V4	475
L3HYPDH	HYKK	A2RU49	456
L3HYPDH	FAM234A	Q9H0X4	454
L3HYPDH	PARS2	Q7L3T8	449
L3HYPDH	UTP11	Q9Y3A2	433
L3HYPDH	APEH	P13798	421
L3HYPDH	OR2AE1	Q8NHA4	419
L3HYPDH	RPL26L1	Q9UNX3	414
L3HYPDH	OPLAH	O14841	410
L3HYPDH	PYCR2	Q96C36	397
L3HYPDH	ZKSCAN5	Q9Y2L8	397

IntAct

18 interactions, top by confidence:

A	B	Type	Score
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
L3HYPDH	CCNE2	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
IP6K3	PROZ	psi-mi:“MI:0914”(association)	0.350
RPL22L1	FAAP100	psi-mi:“MI:0914”(association)	0.350
CPZ	L3HYPDH	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
SRP14	RPSA2	psi-mi:“MI:0914”(association)	0.350
RNASE13	POTEF	psi-mi:“MI:0914”(association)	0.350
CPZ	HSPA8	psi-mi:“MI:0914”(association)	0.350
L3HYPDH	HELZ	psi-mi:“MI:0914”(association)	0.350
L3HYPDH	MAPK13	psi-mi:“MI:0914”(association)	0.350
SLC25A11	FGL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (57): ALDH7A1 (Affinity Capture-MS), MUT (Affinity Capture-MS), GSTK1 (Affinity Capture-MS), UTRN (Affinity Capture-MS), RDH13 (Affinity Capture-MS), CCNE2 (Affinity Capture-MS), ACOT9 (Affinity Capture-MS), CHEK1 (Affinity Capture-MS), DIXDC1 (Affinity Capture-MS), NKIRAS2 (Affinity Capture-MS), POLR3C (Affinity Capture-MS), THUMPD3 (Affinity Capture-MS), L3HYPDH (Affinity Capture-MS), L3HYPDH (Affinity Capture-MS), CCNE2 (Affinity Capture-MS)

ESM2 similar proteins: A0AZQ0, A0B0B8, A0NXQ7, A0NXQ9, A1BBM5, A3M4A9, A5VNS7, A5VZY6, A9AKG8, A9AQW9, A9CKB4, A9M8C0, B0CJW8, B0VB44, B2S9I5, B3D6W2, B4EHE6, B9J8G8, B9JHU6, B9JQV3, B9K4G4, B9R4E3, C5ZMD2, D2AV87, D7A0Y3, Q0B950, Q0B9R9, Q0KJL4, Q1QU06, Q2KD13, Q2T3J4, Q2YPK6, Q3JHA9, Q3SX04, Q4KGU2, Q57F22, Q5LKW3, Q5RC28, Q63NG7, Q7NU77

Diamond homologs: A0AZQ0, A0B0B8, A0NXQ7, A1B195, A1BBM5, A3M4A9, A3PPJ8, A3QFI1, A5VSD5, A5VZY6, A6WXX7, A8DEZ8, A8H392, A9AKG8, A9AQW9, A9CKB4, A9M832, A9WWR5, B0VB44, B2S7L7, B3D6W2, B4EHE6, B9J8G8, B9JHU6, B9R4E3, C5ZMD2, D2AV87, D2QN44, D5SQS4, D7A0Y1, D7A0Y3, E3PTZ4, Q0B950, Q0B9R9, Q17ZY4, Q1QBF3, Q1QU06, Q2T3J4, Q2YLF3, Q3IWG2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	69
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1023 predictions. Top by Δscore:

Variant	Effect	Δscore
14:59475862:CACTT:C	donor_loss	1.0000
14:59475863:ACTTA:A	donor_loss	1.0000
14:59475864:CTTA:C	donor_loss	1.0000
14:59475865:TTAC:T	donor_loss	1.0000
14:59475866:TACC:T	donor_loss	1.0000
14:59475867:A:AC	donor_gain	1.0000
14:59475867:AC:A	donor_gain	1.0000
14:59475867:ACCC:A	donor_loss	1.0000
14:59475868:C:CC	donor_gain	1.0000
14:59475868:C:G	donor_loss	1.0000
14:59475868:CC:C	donor_gain	1.0000
14:59475868:CCCT:C	donor_gain	1.0000
14:59476003:CAAC:C	acceptor_gain	1.0000
14:59476005:ACC:A	acceptor_loss	1.0000
14:59476007:C:CC	acceptor_gain	1.0000
14:59476007:C:CG	acceptor_loss	1.0000
14:59476008:T:C	acceptor_loss	1.0000
14:59476014:A:T	acceptor_gain	1.0000
14:59476210:TTAAA:T	acceptor_gain	1.0000
14:59476211:TAAA:T	acceptor_gain	1.0000
14:59476215:C:CC	acceptor_gain	1.0000
14:59479180:A:AC	donor_gain	1.0000
14:59479180:A:AT	donor_loss	1.0000
14:59479181:C:CA	donor_loss	1.0000
14:59479181:C:CC	donor_gain	1.0000
14:59479351:TCT:T	acceptor_loss	1.0000
14:59479352:C:CC	acceptor_gain	1.0000
14:59479352:CTA:C	acceptor_loss	1.0000
14:59479353:T:C	acceptor_loss	1.0000
14:59479365:G:C	acceptor_gain	1.0000

AlphaMissense

2296 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:59476104:A:C	F263L	0.998
14:59476104:A:T	F263L	0.998
14:59476106:A:G	F263L	0.998
14:59483906:G:C	C137W	0.996
14:59475995:A:C	S271R	0.995
14:59475995:A:T	S271R	0.995
14:59475997:T:G	S271R	0.995
14:59483834:G:C	S161R	0.995
14:59483834:G:T	S161R	0.995
14:59483836:T:G	S161R	0.995
14:59472977:A:C	F351L	0.994
14:59472977:A:T	F351L	0.994
14:59472979:A:G	F351L	0.994
14:59483840:G:C	F159L	0.994
14:59483840:G:T	F159L	0.994
14:59483842:A:G	F159L	0.994
14:59484035:G:C	F94L	0.994
14:59484035:G:T	F94L	0.994
14:59484037:A:G	F94L	0.994
14:59475883:C:A	G309W	0.993
14:59475969:C:G	R280P	0.993
14:59476001:G:C	D269E	0.992
14:59476001:G:T	D269E	0.992
14:59484003:C:T	G105D	0.992
14:59484036:A:G	F94S	0.992
14:59484220:G:T	R33S	0.992
14:59483822:G:C	F165L	0.991
14:59483822:G:T	F165L	0.991
14:59483824:A:G	F165L	0.991
14:59483907:C:T	C137Y	0.991

dbSNP variants (sampled 300 via entrez): RS1000114168 (14:59467607 C>T), RS1000137923 (14:59496126 G>T), RS1000147558 (14:59506514 C>T), RS1000204741 (14:59470907 C>T), RS1000288459 (14:59484237 G>A), RS1000309126 (14:59486240 C>G,T), RS1000364153 (14:59499818 C>G), RS1000385394 (14:59477654 T>A,G), RS1000515146 (14:59503947 G>A), RS1000518402 (14:59481115 A>G), RS1000581182 (14:59468645 C>T), RS1000713568 (14:59469062 G>C), RS1000715687 (14:59477929 T>A), RS1000726968 (14:59484697 G>A,C,T), RS1000779507 (14:59484838 A>C)

Disease associations

OMIM: gene MIM:614811 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_89	Brain morphology (MOSTest)	1.000000e-76

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression	1
ferrous chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	increases expression	1
Calcitriol	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	increases expression	1
Nickel	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Vanadates	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation, increases expression	1

Clinical trials (associated diseases)

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