PRODH2

Summary

PRODH2 (proline dehydrogenase 2, HGNC:17325) is a protein-coding gene on chromosome 19q13.12, encoding Hydroxyproline dehydrogenase (Q9UF12). Dehydrogenase that converts trans-4-L-hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate (Hyp) using ubiquinone-10 as the terminal electron acceptor.

The protein encoded by this gene catalyzes the first step in the catabolism of trans-4-hydroxy-L-proline, an amino acid derivative obtained through food intake and collagen turnover. One of the downstream products of this catabolism is glyoxylate, which in people with disorders of glyoxalate metabolism can lead to an increase in oxalate levels and the formation of calcium-oxalate kidney stones. Therefore, this gene may serve as a therapeutic target against primary hyperoxalurias (PH). This gene is similar to proline dehydrogenase (oxidase) 1, a mitochondrial enzyme that catalyzes the first step in proline catabolism.

Source: NCBI Gene 58510 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hydroxyprolinemia (Limited, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 113 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_021232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17325
Approved symbol	PRODH2
Name	proline dehydrogenase 2
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	HSPOX1
Ensembl gene	ENSG00000250799
Ensembl biotype	protein_coding
OMIM	616377
Entrez	58510

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 3 retained_intron

ENST00000301175, ENST00000587695, ENST00000587808, ENST00000588266, ENST00000589835, ENST00000591694, ENST00000653904, ENST00000881785, ENST00000881786, ENST00000881787, ENST00000881788, ENST00000881789, ENST00000881790, ENST00000881791, ENST00000881792, ENST00000881793

RefSeq mRNA: 4 — MANE Select: NM_021232 NM_001378292, NM_001378293, NM_001378294, NM_021232

CCDS: CCDS12478

Canonical transcript exons

ENST00000653904 — 10 exons

Exon	Start	End
ENSE00001057244	35812360	35812556
ENSE00001057247	35812134	35812272
ENSE00001057248	35811962	35812048
ENSE00001057302	35807041	35807121
ENSE00001057309	35806675	35806830
ENSE00003466909	35806430	35806596
ENSE00003545984	35802968	35803078
ENSE00003589667	35802191	35802276
ENSE00003877097	35812632	35812845
ENSE00003900647	35799988	35800222

Expression profiles

Bgee: expression breadth ubiquitous, 102 present calls, max score 98.32.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2746 / max 90.7952, expressed in 39 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180580	0.1071	21
180582	0.1006	20
180581	0.0670	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.32	gold quality
liver	UBERON:0002107	95.61	gold quality
adult mammalian kidney	UBERON:0000082	95.40	gold quality
nephron tubule	UBERON:0001231	93.59	gold quality
kidney epithelium	UBERON:0004819	93.17	gold quality
adult organism	UBERON:0007023	91.96	gold quality
renal glomerulus	UBERON:0000074	90.94	gold quality
metanephric glomerulus	UBERON:0004736	90.82	gold quality
kidney	UBERON:0002113	90.20	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.65	silver quality
renal medulla	UBERON:0000362	84.23	gold quality
cortex of kidney	UBERON:0001225	83.29	gold quality
metanephros	UBERON:0000081	80.68	gold quality
gingival epithelium	UBERON:0001949	78.91	gold quality
cardia of stomach	UBERON:0001162	78.16	gold quality
sperm	CL:0000019	78.14	silver quality
male germ cell	CL:0000015	77.40	silver quality
vena cava	UBERON:0004087	77.04	silver quality
triceps brachii	UBERON:0001509	76.11	gold quality
gluteal muscle	UBERON:0002000	75.97	gold quality
body of pancreas	UBERON:0001150	74.80	gold quality
vastus lateralis	UBERON:0001379	74.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	74.42	silver quality
lateral globus pallidus	UBERON:0002476	73.89	gold quality
quadriceps femoris	UBERON:0001377	73.49	gold quality
cartilage tissue	UBERON:0002418	72.79	silver quality
nasal cavity epithelium	UBERON:0005384	72.71	gold quality
substantia nigra pars reticulata	UBERON:0001966	72.65	silver quality
saphenous vein	UBERON:0007318	72.60	gold quality
trabecular bone tissue	UBERON:0002483	72.47	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	2652.60
E-GEOD-131882	yes	2406.30
E-CURD-135	no	1319.13
E-ANND-3	no	3.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1A, HNF4A

Literature-anchored findings (GeneRIF, showing 3)

• OH-POX plays a role analogous to POX in growth regulation, ROS generation, and activation of the apoptotic cascade (PMID:18287100)
• PRODH, but not PRODH2, expression is under the control of p53 family members, specifically p53 and p73. (PMID:23861960)
• Data suggest that residues 157-515 of PRODH2 contain catalytic core with one FAD molecule; PRODH2 most likely utilizes coenzyme Q10 as terminal electron acceptor in vivo; PRODH2 exhibits substrate specificity for hydroxyproline over proline. (PMID:25697095)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:92040	ENSDARG00000021154
mus_musculus	Prodh2	ENSMUSG00000036892
rattus_norvegicus	Prodh2	ENSRNOG00000057578

Paralogs (2): PRODH (ENSG00000100033), (ENSG00000277196)

Protein

Protein identifiers

Hydroxyproline dehydrogenase — Q9UF12 (reviewed: Q9UF12)

Alternative names: Kidney and liver proline oxidase 1, Probable proline dehydrogenase 2, Probable proline oxidase 2

All UniProt accessions (3): Q9UF12, K7EJK5, S4R3D8

UniProt curated annotations — full annotation on UniProt →

Function. Dehydrogenase that converts trans-4-L-hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate (Hyp) using ubiquinone-10 as the terminal electron acceptor. Can also use proline as a substrate but with a very much lower efficiency. Does not react with other diastereomers of Hyp: trans-4-D-hydroxyproline and cis-4-L-hydroxyproline. Ubiquininone analogs such as menadione, duroquinone and ubiquinone-1 react more efficiently than oxygen as the terminal electron acceptor during catalysis.

Activity regulation. Hydroproxyproline dehydrogenase activity is inhibited by THFA,(1R,3R)3-OH-cyclopentane-COOH and 5-OH-1H-pyrazole-3-COOH.

Similarity. Belongs to the proline oxidase family.

RefSeq proteins (4): NP_001365221, NP_001365222, NP_001365223, NP_067055* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002872	Proline_DH_dom	Domain
IPR015659	Proline_oxidase	Family
IPR029041	FAD-linked_oxidoreductase-like	Homologous_superfamily

Pfam: PF01619

Enzyme classification (BRENDA):

• EC 1.5.5.3 — hydroxyproline dehydrogenase (BRENDA: 3 organisms, 11 substrates, 5 inhibitors, 4 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
COENZYME Q1	0.124	1
DUROQUINONE	0.143	1
MENAQUINONE	0.025	1
TRANS-4-HYDROXY-L-PROLINE	200	1

Catalyzed reactions (Rhea), 2 shown:

• L-proline + a quinone = (S)-1-pyrroline-5-carboxylate + a quinol + H(+) (RHEA:23784)
• trans-4-hydroxy-L-proline + a quinone = (3R,5S)-1-pyrroline-3-hydroxy-5-carboxylate + a quinol + H(+) (RHEA:52512)

UniProt features (4 total): sequence variant 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UF12-F1	87.87	0.66

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): 310

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-389661	Glyoxylate metabolism and glycine degradation
R-HSA-70688	Proline catabolism

MSigDB gene sets: 84 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GNF2_HPN, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, HNF1_Q6, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, HNF4_DR1_Q3, GOCC_MITOCHONDRIAL_ENVELOPE, PPAR_DR1_Q2, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, GOBP_AMINO_ACID_CATABOLIC_PROCESS

GO Biological Process (3): L-proline catabolic process (GO:0006562), obsolete L-proline catabolic process to L-glutamate (GO:0010133), L-proline metabolic process (GO:0006560)

GO Molecular Function (4): proline dehydrogenase activity (GO:0004657), oxidoreductase activity, acting on the CH-NH group of donors (GO:0016645), FAD binding (GO:0071949), oxidoreductase activity (GO:0016491)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-proline metabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
oxidoreductase activity, acting on the CH-NH group of donors, quinone or similar compound as acceptor	1
oxidoreductase activity	1
flavin adenine dinucleotide binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1

Protein interactions and networks

STRING

1712 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRODH2	HOGA1	Q86XE5	611
PRODH2	ALDH4A1	P30038	603
PRODH2	AGXT	P21549	594
PRODH2	GRHPR	Q9UBQ7	588
PRODH2	DGCR2	P98153	538
PRODH2	OVOL3	O00110	531
PRODH2	OR6C6	A6NF89	520
PRODH2	ZDHHC8	Q9ULC8	506
PRODH2	TBX1	O43435	505
PRODH2	HAO1	Q9UJM8	505
PRODH2	COMT	P21964	496
PRODH2	ALDH18A1	P54886	492
PRODH2	DGCR6	Q14129	476
PRODH2	UFD1	Q92890	474
PRODH2	FEM1A	Q9BSK4	474

IntAct

2 interactions, top by confidence:

A	B	Type	Score
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350

BioGRID (1): PRODH2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A1L1J9, A1L504, A6NH21, A8WCG0, B0BNG2, F1RMN2, O43292, O75908, O76062, O77759, O88496, O88908, O89109, P38435, Q07175, Q0P4Y8, Q49LS0, Q5KR61, Q5RF50, Q5XK03, Q5ZKZ9, Q643R3, Q658P3, Q6MG14, Q6NVG1, Q767L9, Q7TN60, Q7TPN3, Q7TQM4, Q7ZWN0, Q8BKF1, Q8C3X8, Q8IUH8, Q8IZY2, Q8N130, Q8VC65, Q8WMV1, Q91YD1, Q9BU23

Diamond homologs: A6QQ74, O43272, O45228, P09368, Q04499, Q148G5, Q2V057, Q6PAY6, Q8VCZ9, Q9UF12, Q9WU79, O74524, Q6NKX1, Q86H28, Q9XB58, P92983

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	92
Likely benign	14
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2579207	GRCh38/hg38 19q13.12(chr19:35811865-35846292)x0	Pathogenic

SpliceAI

1458 predictions. Top by Δscore:

Variant	Effect	Δscore
19:35802967:CCG:C	donor_gain	1.0000
19:35807131:A:T	acceptor_gain	1.0000
19:35812358:A:AC	donor_gain	1.0000
19:35812358:AC:A	donor_gain	1.0000
19:35812359:C:CC	donor_gain	1.0000
19:35812359:CC:C	donor_gain	1.0000
19:35812359:CCCA:C	donor_gain	1.0000
19:35802977:G:A	donor_gain	0.9900
19:35806827:CATA:C	acceptor_gain	0.9900
19:35806829:TA:T	acceptor_gain	0.9900
19:35806831:C:CC	acceptor_gain	0.9900
19:35807120:TT:T	acceptor_gain	0.9900
19:35807122:C:CC	acceptor_gain	0.9900
19:35807123:T:C	acceptor_loss	0.9900
19:35807133:C:CT	acceptor_gain	0.9900
19:35812049:C:CC	acceptor_gain	0.9900
19:35812354:ACT:A	donor_loss	0.9900
19:35812358:ACC:A	donor_gain	0.9900
19:35812359:CCC:C	donor_gain	0.9900
19:35812362:A:AC	donor_gain	0.9900
19:35812363:C:CC	donor_gain	0.9900
19:35812363:CT:C	donor_gain	0.9900
19:35807118:GGTT:G	acceptor_gain	0.9800
19:35807119:GTT:G	acceptor_gain	0.9800
19:35807130:C:CT	acceptor_gain	0.9800
19:35807134:A:T	acceptor_gain	0.9800
19:35811956:CCTTA:C	donor_loss	0.9800
19:35811957:CTTAC:C	donor_loss	0.9800
19:35811958:TTACC:T	donor_loss	0.9800
19:35811959:TA:T	donor_loss	0.9800

AlphaMissense

2911 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35812479:A:C	F160L	0.981
19:35812479:A:T	F160L	0.981
19:35812481:A:G	F160L	0.981
19:35807060:C:G	R296P	0.968
19:35812710:C:A	K108N	0.967
19:35812710:C:G	K108N	0.967
19:35806826:G:T	A304D	0.964
19:35812474:G:T	A162D	0.956
19:35800197:C:A	K484N	0.955
19:35800197:C:G	K484N	0.955
19:35802234:G:C	F461L	0.955
19:35802234:G:T	F461L	0.955
19:35802236:A:G	F461L	0.955
19:35800183:C:A	G489V	0.948
19:35812490:A:C	Y157D	0.948
19:35807061:G:T	R296S	0.944
19:35812230:A:C	C214W	0.944
19:35800183:C:T	G489D	0.938
19:35800184:C:G	G489R	0.933
19:35812471:C:A	G163V	0.933
19:35812232:A:G	C214R	0.921
19:35806528:C:A	K377N	0.918
19:35806528:C:G	K377N	0.918
19:35812432:A:G	L176P	0.918
19:35812471:C:T	G163D	0.917
19:35806537:G:C	F374L	0.913
19:35806537:G:T	F374L	0.913
19:35806539:A:G	F374L	0.913
19:35812480:A:G	F160S	0.907
19:35812231:C:T	C214Y	0.906

dbSNP variants (sampled 300 via entrez): RS1000167577 (19:35811371 A>T), RS1000469301 (19:35801051 C>T), RS1000490464 (19:35802036 C>T), RS1000726139 (19:35806188 T>A), RS1001096185 (19:35806524 C>T), RS1001417042 (19:35811687 G>A), RS1001469079 (19:35799880 C>T), RS1001511532 (19:35805963 G>A), RS1001699527 (19:35805267 A>G), RS1002039263 (19:35801589 G>A), RS1002127187 (19:35804915 G>A), RS1002199852 (19:35808939 C>T), RS1002253748 (19:35809173 G>A), RS1002455433 (19:35814432 C>A,G,T), RS1002624004 (19:35804674 C>T)

Disease associations

OMIM: gene MIM:616377 | disease phenotypes: MIM:256300

GenCC curated gene-disease

Disease	Classification	Inheritance
hydroxyprolinemia	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
hydroxyprolinemia	Limited	AR

Mondo (2): congenital nephrotic syndrome, Finnish type (MONDO:0009732), hydroxyprolinemia (MONDO:0009374)

Orphanet (1): Congenital nephrotic syndrome, Finnish type (Orphanet:839)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_277	Brain morphology (MOSTest)	2.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562669	Hydroxyprolinemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523486 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression	3
Resveratrol	increases expression, affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	decreases expression	2
sotorasib	decreases expression, affects cotreatment	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
nivalenol	increases expression	1
CGP 52608	increases reaction, affects binding	1
K 7174	decreases expression	1
lipopolysaccharide, Helicobacter pylori	increases expression	1
clothianidin	increases expression	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Clorgyline	increases expression	1
Diethylnitrosamine	decreases expression	1
Fluorouracil	decreases expression, affects response to substance	1
Phenobarbital	affects expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Quercetin	decreases expression	1
Silicon Dioxide	decreases expression	1
Triclosan	increases expression	1
Urethane	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4418407	Binding	Inhibition of human recombinant HYPDH expressed in Escherichia coli using hydroxyproline as substrate preincubated for 5 mins followed by substrate addition in presence of FAD as cofactor	Hypdh inhibitors and methods of use for the treatment of kidney stones

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening