APIP

Summary

APIP (APAF1 interacting protein, HGNC:17581) is a protein-coding gene on chromosome 11p13, encoding Methylthioribulose-1-phosphate dehydratase (Q96GX9). Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P).

Enables identical protein binding activity; methylthioribulose 1-phosphate dehydratase activity; and zinc ion binding activity. Involved in several processes, including obsolete L-methionine salvage from methylthioadenosine; protein homotetramerization; and pyroptotic inflammatory response. Located in cytoplasm.

Source: NCBI Gene 51074 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 62 total
• GTEx eGene: eQTL in 50 tissues, sQTL in 50 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.42 (unconstrained)
• MANE Select transcript: NM_015957
• Notable: 62 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17581
Approved symbol	APIP
Name	APAF1 interacting protein
Location	11p13
Locus type	gene with protein product
Status	Approved
Aliases	CGI-29, Mmrp19, APIP2
Ensembl gene	ENSG00000149089
Ensembl biotype	protein_coding
OMIM	612491
Entrez	51074

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 17 protein_coding, 11 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000395787

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1

ENST00000395787, ENST00000527830, ENST00000532428, ENST00000901543, ENST00000901544, ENST00000901545, ENST00000901546, ENST00000937716, ENST00000937717, ENST00000937718, ENST00000937719, ENST00000965075, ENST00000965076, ENST00000973626, ENST00000973627, ENST00000973628, ENST00001060244, ENST00001060246, ENST00001060247, ENST00001060251, ENST00001102638, ENST00001102639, ENST00001102640, ENST00001102641, ENST00001102642, ENST00001102643, ENST00001102644, ENST00001102645, ENST00001139797

RefSeq mRNA: 1 — MANE Select: NM_015957 NM_015957

CCDS: CCDS7895

Canonical transcript exons

ENST00000395787 — 7 exons

Exon	Start	End
ENSE00000988738	34895010	34895110
ENSE00002192018	34882295	34882816
ENSE00002198995	34916228	34916379
ENSE00003460374	34890504	34890552
ENSE00003478274	34888752	34888869
ENSE00003659871	34888293	34888428
ENSE00003669096	34883337	34883504

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 93.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.5014 / max 325.6449, expressed in 1821 samples.

Highest expression (Bgee): C1 segment of cervical spinal cord, hindlimb stylopod muscle, adrenal gland, corpus callosum, adrenal gland cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

APIP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 50 tissues and its splicing (sQTL) in 50 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 100 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	1.1e-275	+1.40	11:34895725:C:T
Artery Tibial	sqtl	3.1e-237	+1.44	11:34895725:C:T
Adipose Subcutaneous	sqtl	8.2e-221	+1.42	11:34895725:C:T
Nerve Tibial	sqtl	3.5e-197	+1.42	11:34895725:C:T
Cells Cultured fibroblasts	sqtl	2.0e-184	+1.39	11:34895725:C:T
Thyroid	sqtl	1.1e-179	+1.29	11:34886069:CTCCT:C
Adipose Visceral Omentum	sqtl	2.1e-156	+1.34	11:34895725:C:T
Thyroid	eqtl	1.8e-155	+1.16	11:34895725:C:T
Skin Sun Exposed Lower leg	sqtl	2.8e-151	+1.26	11:34919279:CTG:C
Esophagus Muscularis	sqtl	8.1e-144	+1.47	11:34895725:C:T
Artery Aorta	sqtl	3.7e-139	+1.36	11:34895725:C:T
Lung	sqtl	1.9e-137	+1.17	11:34895110:C:T
Breast Mammary Tissue	sqtl	4.6e-130	+1.39	11:34895725:C:T
Nerve Tibial	eqtl	9.2e-125	+1.07	11:34890144:C:T
Heart Atrial Appendage	sqtl	1.3e-104	+1.39	11:34886069:CTCCT:C
Esophagus Muscularis	eqtl	2.7e-101	+1.08	11:34930611:T:C
Skin Sun Exposed Lower leg	eqtl	5.3e-96	+0.85	11:34890144:C:T
Esophagus Gastroesophageal Junction	sqtl	7.2e-94	+1.42	11:34895725:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.5e-84	+0.88	11:34877621:TAG:T
Adipose Subcutaneous	eqtl	1.0e-83	+0.70	11:34890144:C:T

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
119260	28.1409	1820
119263	0.5516	336
119261	0.4922	276
119262	0.3060	134
206249	0.0107	8

Top tissues by expression

showing 100 of 134 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	93.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.61	gold quality
right adrenal gland	UBERON:0001233	93.31	gold quality
corpus callosum	UBERON:0002336	93.10	gold quality
right adrenal gland cortex	UBERON:0035827	93.05	gold quality
monocyte	CL:0000576	92.80	gold quality
skeletal muscle tissue	UBERON:0001134	92.74	gold quality
left adrenal gland	UBERON:0001234	92.55	gold quality
adrenal tissue	UBERON:0018303	92.40	gold quality
leukocyte	CL:0000738	92.32	gold quality
muscle of leg	UBERON:0001383	92.25	gold quality
adrenal gland	UBERON:0002369	92.16	gold quality
left adrenal gland cortex	UBERON:0035825	92.14	gold quality
gastrocnemius	UBERON:0001388	91.99	gold quality
muscle tissue	UBERON:0002385	91.78	gold quality
substantia nigra	UBERON:0002038	91.20	gold quality
gall bladder	UBERON:0002110	90.86	gold quality
saliva-secreting gland	UBERON:0001044	90.85	gold quality
minor salivary gland	UBERON:0001830	90.54	gold quality
endometrium	UBERON:0001295	90.49	gold quality
body of pancreas	UBERON:0001150	90.22	gold quality
fundus of stomach	UBERON:0001160	90.16	gold quality
mucosa of transverse colon	UBERON:0004991	90.14	gold quality
islet of Langerhans	UBERON:0000006	90.02	gold quality
rectum	UBERON:0001052	90.02	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.00	gold quality
body of stomach	UBERON:0001161	89.85	gold quality
pancreas	UBERON:0001264	89.75	gold quality
ganglionic eminence	UBERON:0004023	89.64	gold quality
omental fat pad	UBERON:0010414	89.59	gold quality
Ammon’s horn	UBERON:0001954	89.56	gold quality
adipose tissue	UBERON:0001013	89.50	gold quality
ventricular zone	UBERON:0003053	89.43	gold quality
thoracic mammary gland	UBERON:0005200	89.36	gold quality
smooth muscle tissue	UBERON:0001135	89.33	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.32	gold quality
vermiform appendix	UBERON:0001154	89.27	gold quality
hypothalamus	UBERON:0001898	89.23	gold quality
lymph node	UBERON:0000029	89.00	gold quality
prostate gland	UBERON:0002367	88.78	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.75	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.71	gold quality
amygdala	UBERON:0001876	88.69	gold quality
calcaneal tendon	UBERON:0003701	88.66	gold quality
lower esophagus	UBERON:0013473	88.66	gold quality
stomach	UBERON:0000945	88.56	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.55	gold quality
tibial artery	UBERON:0007610	88.54	gold quality
popliteal artery	UBERON:0002250	88.53	gold quality
heart left ventricle	UBERON:0002084	88.50	gold quality
colon	UBERON:0001155	88.47	gold quality
temporal lobe	UBERON:0001871	88.45	gold quality
body of uterus	UBERON:0009853	88.45	gold quality
myometrium	UBERON:0001296	88.44	gold quality
adenohypophysis	UBERON:0002196	88.43	gold quality
adult mammalian kidney	UBERON:0000082	88.25	gold quality
transverse colon	UBERON:0001157	88.23	gold quality
heart	UBERON:0000948	88.21	gold quality
endocervix	UBERON:0000458	88.14	gold quality
metanephros cortex	UBERON:0010533	88.03	gold quality
left coronary artery	UBERON:0001626	88.01	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.01	gold quality
tonsil	UBERON:0002372	88.00	gold quality
right lung	UBERON:0002167	87.95	gold quality
kidney	UBERON:0002113	87.92	gold quality
cortex of kidney	UBERON:0001225	87.88	gold quality
thyroid gland	UBERON:0002046	87.87	gold quality
putamen	UBERON:0001874	87.84	gold quality
lung	UBERON:0002048	87.80	gold quality
intestine	UBERON:0000160	87.77	gold quality
caudate nucleus	UBERON:0001873	87.66	gold quality
upper lobe of left lung	UBERON:0008952	87.65	gold quality
left lobe of thyroid gland	UBERON:0001120	87.64	gold quality
thoracic aorta	UBERON:0001515	87.57	gold quality
ascending aorta	UBERON:0001496	87.54	gold quality
right atrium auricular region	UBERON:0006631	87.46	gold quality
mucosa of stomach	UBERON:0001199	87.27	gold quality
placenta	UBERON:0001987	87.21	gold quality
tibial nerve	UBERON:0001323	87.20	gold quality
brain	UBERON:0000955	87.08	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.06	gold quality
pituitary gland	UBERON:0000007	87.04	gold quality
cerebral cortex	UBERON:0000956	87.03	gold quality
multicellular organism	UBERON:0000468	86.94	gold quality
duodenum	UBERON:0002114	86.94	gold quality
right lobe of thyroid gland	UBERON:0001119	86.91	gold quality
prefrontal cortex	UBERON:0000451	86.80	gold quality
esophagus	UBERON:0001043	86.79	gold quality
anterior cingulate cortex	UBERON:0009835	86.78	gold quality
fallopian tube	UBERON:0003889	86.77	gold quality
right ovary	UBERON:0002118	86.76	gold quality
urinary bladder	UBERON:0001255	86.75	gold quality
descending thoracic aorta	UBERON:0002345	86.72	gold quality
ovary	UBERON:0000992	86.48	gold quality
left ovary	UBERON:0002119	86.47	gold quality
spleen	UBERON:0002106	86.44	gold quality
ectocervix	UBERON:0012249	86.36	gold quality
nucleus accumbens	UBERON:0001882	86.35	gold quality
apex of heart	UBERON:0002098	86.35	gold quality
frontal cortex	UBERON:0001870	86.23	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.63
E-MTAB-6108	no	134.17
E-MTAB-6379	no	132.03

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	61.5	medium
Tongue	tissue	35.7
Salivary gland	tissue	29.9	high
Thymus	tissue	29.1
Adipose tissue	tissue	28.5	low
Spinal cord	tissue	28.2
Kidney	tissue	25.2	medium
Adrenal gland	tissue	23.9	high
Thyroid gland	tissue	23.1	low
Periaqueductal gray	tissue	22.9
Pons	tissue	22.4
Medulla oblongata	tissue	22.3
Seminal vesicle	tissue	22.2	medium
Substantia nigra	tissue	21.7
Midbrain	tissue	20.7
Thalamus	tissue	20.0
Superior colliculi	tissue	20.0
Lung	tissue	20.0	medium
Corpus callosum	tissue	19.8
Appendix	tissue	19.5	medium
Breast	tissue	19.3	medium
Lymph node	tissue	18.9	low
Heart muscle	tissue	18.7	medium
Colon	tissue	18.7	high
Hypothalamus	tissue	18.5
Rectum	tissue	18.4	medium
Liver	tissue	18.2	medium
Urinary bladder	tissue	17.9	high
Gallbladder	tissue	17.4	high
Cervix	tissue	17.0	not detected
Stomach 1	tissue	16.9	high
Ovary	tissue	16.6	not detected
Pancreas	tissue	16.2	high
Fallopian tube	tissue	16.2	medium
Frontal cortex	tissue	16.0
Septum	tissue	15.9
Prostate	tissue	15.8	high
Retina	tissue	15.6
Small intestine	tissue	15.4	high
Tonsil	tissue	15.3	low
Parathyroid gland	tissue	14.9	low
Hippocampal formation	tissue	14.9
Spleen	tissue	14.6	not detected
Epididymis	tissue	14.1	not detected
Endometrium 1	tissue	14.0	medium
Bone marrow	tissue	13.6	low
Caudate putamen	tissue	13.6
Locus coeruleus	tissue	13.2
Cerebral cortex	tissue	13.0	low
Esophagus	tissue	13.0	low
Choroid plexus	tissue	13.0
Occipital cortex	tissue	13.0
Putamen	tissue	12.8
Duodenum	tissue	12.8	medium
Entorhinal cortex	tissue	12.7
Basal ganglia	tissue	12.6	low
Somatosensory cortex	tissue	12.6
Placenta	tissue	12.5	low
Amygdala	tissue	12.1
Nucleus accumbens	tissue	12.1

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (28.2), Dorsal spinal cord (26.3), Corpus callosum, genu (white matter) (26.2), Cerebellar white matter (24.9), Corpus callosum, splenium (white matter) (24.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting APIP by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 35 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-6516-5P	98.42	70.19	1551
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-3921	97.81	67.45	1431

Functional genomics

gnomAD constraint: pLI 2.27e-09, LOEUF 1.42, missense Z 0.733 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000395787 — one region, missense o/e 0.83.

Literature-anchored findings (GeneRIF, showing 9)

• APIP functions to inhibit muscle ischemic damage by binding to Apaf-1 in the Apaf-1/caspase-9 apoptosis pathway. (PMID:15262985)
• The down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in non-small cell lung cancer cells. (PMID:22407486)
• A polymorphism associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in Salmonella. (PMID:22837397)
• human APIP was overproduced in Escherichia coli, purified and crystallized. An X-ray diffraction data set was collected to 2.40 A resolution (PMID:23192037)
• these results confirm the involvement of APIP in the methionine salvage pathway, which plays a key role in many biological functions like cancer, apoptosis, microbial proliferation and inflammation. (PMID:23285211)
• APIP/MtnB functions as a cell death inhibitor independently of its MtnB enzyme activity for apoptosis induced by either hypoxia or etoposide, but dependently for caspase-1-induced pyroptosis (PMID:24367089)
• Results suggest that APIP stimulates cell proliferation via ERBB3, acting in conjunction with ERBB2, in gastric cancer cells. (PMID:26942872)
• APIP is crucial for cardioprotection against myocardial infarction by virtue of binding to and stabilizing ADORA2B, thereby dampening ischemic heart injury. (PMID:31263105)
• APIP regulated by YAP propels methionine cycle and metastasis in head and neck squamous cell carcinoma. (PMID:38423248)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	apip	ENSDARG00000003132
mus_musculus	Apip	ENSMUSG00000010911
rattus_norvegicus	Apip	ENSRNOG00000007446
drosophila_melanogaster	CG11134	FBGN0030518
caenorhabditis_elegans		WBGENE00013870

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1926788) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating serum albumin level	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Histoplasma mississippiense	A6RAS3	100.0%	Diamond
Aspergillus fumigatus A1163	B0Y4N9	100.0%	Diamond
Saccharomyces cerevisiae RM11-1a	B3LQB9	100.0%	Diamond
Drosophila sechellia	B4IG61	100.0%	Diamond
Drosophila simulans	B4R4E9	100.0%	Diamond
Saccharomyces cerevisiae AWRI1631	B5VLI6	100.0%	Diamond
Aspergillus flavus NRRL3357	B8NSW2	100.0%	Diamond
Histoplasma capsulatum H143	C6H2R1	100.0%	Diamond
Escherichia coli K-12	P0AB87	100.0%	Diamond
Shigella flexneri	P0AB88	100.0%	Diamond
Cryptococcus deneoformans JEC21	P0CM14	100.0%	Diamond
Cryptococcus deneoformans B-3501A	P0CM15	100.0%	Diamond
Aspergillus oryzae RIB40	Q2UUH5	100.0%	Diamond
Aspergillus fumigatus Af293	Q4WQH4	100.0%	Diamond
Saccharomyces cerevisiae YJM789	A6ZPY9	99.6%	Diamond
Drosophila erecta	B3NVZ7	99.6%	Diamond
Oryza sativa Indica Group	B8BKI7	99.6%	Diamond
Histoplasma capsulatum G186AR	C0NN25	99.6%	Diamond
Paracoccidioides brasiliensis Pb03	C0S4Z7	99.6%	Diamond
Paracoccidioides brasiliensis Pb18	C1G3Q0	99.6%	Diamond
Candida albicans WO-1	C4YRG6	99.6%	Diamond
Blastomyces dermatitidis ER-3	C5GGA4	99.6%	Diamond
Blastomyces gilchristii SLH14081	C5JIC2	99.6%	Diamond
Saccharomyces cerevisiae JAY291	C7GKY0	99.6%	Diamond
Oryza sativa Japonica Group	Q2R483	99.6%	Diamond
Candida albicans SC5314	Q5AG73	99.6%	Diamond
Escherichia coli CFT073	Q8FEF0	99.5%	Diamond
Escherichia coli O157:H7	Q8X6R8	99.5%	Diamond
Paracoccidioides lutzii Pb01	C1H861	99.2%	Diamond
Drosophila yakuba	B4Q2F5	99.1%	Diamond
Saccharomyces cerevisiae S288C	P47095	98.8%	Diamond
Xenopus tropicalis	Q5FW37	98.3%	Diamond
Xenopus laevis	Q6NU29	98.3%	Diamond
Aspergillus fischeri NRRL 181	A1CW59	97.9%	Diamond
Pectobacterium carotovorum subsp. carotovorum PC1	C6DCZ4	97.6%	Diamond
Pectobacterium atrosepticum SCRI1043	Q6D1G1	97.6%	Diamond
Drosophila ananassae	B3MW09	96.9%	Diamond
Leishmania infantum	A4I3R0	96.0%	Diamond
Leishmania major	Q4Q882	96.0%	Diamond
Candida dubliniensis CD36	B9WHK1	95.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PDHX	protein-coding	8050
MIR1343	ncRNA	100616437
LINC02707	ncRNA	105376623
EHF	protein-coding	26298
CD44-DT	ncRNA	100507144

Protein

Protein identifiers

Methylthioribulose-1-phosphate dehydratase — Q96GX9 (reviewed: Q96GX9)

Alternative names: APAF1-interacting protein

All UniProt accessions (2): Q96GX9, S4R3D6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the dehydration of methylthioribulose-1-phosphate (MTRu-1-P) into 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P). Functions in the methionine salvage pathway, which plays a key role in cancer, apoptosis, microbial proliferation and inflammation. May inhibit the CASP1-related inflammatory response (pyroptosis), the CASP9-dependent apoptotic pathway and the cytochrome c-dependent and APAF1-mediated cell death.

Subunit / interactions. Homotetramer. Interacts with APAF1. May interact with CASP1.

Subcellular location. Cytoplasm.

Tissue specificity. Isoform 1 is ubiquitously expressed. Isoform 2 is expressed at lower levels and detected in heart, brain, pancreas, liver, placenta, skeletal muscle and kidney.

Cofactor. Binds 1 zinc ion per subunit.

Pathway. Amino-acid biosynthesis; L-methionine biosynthesis via salvage pathway; L-methionine from S-methyl-5-thio-alpha-D-ribose 1-phosphate: step 2/6.

Similarity. Belongs to the aldolase class II family. MtnB subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96GX9-1	1, Long	yes
Q96GX9-3	2, Short

RefSeq proteins (1): NP_057041* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001303	Aldolase_II/adducin_N	Domain
IPR017714	MethylthioRu-1-P_deHdtase_MtnB	Family
IPR027514	Salvage_MtnB_euk	Family
IPR036409	Aldolase_II/adducin_N_sf	Homologous_superfamily

Pfam: PF00596

Enzyme classification (BRENDA)

• EC 4.2.1.109 — methylthioribulose 1-phosphate dehydratase (BRENDA: 10 organisms, 5 substrates, 0 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
S-METHYL-5-THIO-D-RIBULOSE 1-PHOSPHATE	0.0089	1

Catalyzed reactions (Rhea)

• 5-(methylsulfanyl)-D-ribulose 1-phosphate = 5-methylsulfanyl-2,3-dioxopentyl phosphate + H2O (RHEA:15549)

UniProt features (46 total): mutagenesis site 11, helix 10, strand 9, sequence variant 4, binding site 4, sequence conflict 2, turn 2, chain 1, active site 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
4M6R	Structural and biochemical basis for the inhibition of cell death by APIP, a methionine …	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96GX9-F1	93.41	0.90

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Lyases, Metabolic proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IH approved · IF approved

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)

Position	Role
139	proton donor/acceptor

Ligand- & substrate-binding residues (4)

Position	Role
97	substrate
115	Zn(2+)
117	Zn(2+)
195	Zn(2+)

Post-translational modifications (1)

Type	Positions
Phosphoserine	87

Mutagenesis-validated functional residues (11)

Position	Phenotype
84	does not affect ability of cells to grow in media where methionine is replaced by 5-methylthioadenosine; when associated with a,d-87 and …
87	does not affect ability of cells to grow in media where methionine is replaced by 5-methylthioadenosine; when associated with a,d-84 and …
89	does not affect ability of cells to grow in media where methionine is replaced by 5-methylthioadenosine; when associated with a,d-84 and …
96	mildly reduced enzyme activity.
97	acts as a dominant negative mutant; unable to use 5’-methylthioadenosine as source of methionine. does not affect the ability to bind casp1 …
97	almost complete loss of enzyme activity. abolishes protection against pyroptosis. no effect on anti-apoptotic activity.
115	almost complete loss of enzyme activity. abolishes protection against pyroptosis. no effect on anti-apoptotic activity.
115	impaired ability of cells to grow in media where methionine is replaced by 5-methylthioadenosine; when associated with a-117 and a-195 …
117	impaired ability of cells to grow in media where methionine is replaced by 5-methylthioadenosine; when associated with a-115 and a-195.
139	almost complete loss of enzyme activity. abolishes protection against pyroptosis. no effect on anti-apoptotic activity.
195	impaired ability of cells to grow in media where methionine is replaced by 5-methylthioadenosine; when associated with 87-a–a-89.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 11; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

11 pathways:

ID	Pathway	Evidence
R-HSA-111458	Formation of apoptosome	curated
R-HSA-9627069	Regulation of the apoptosome activity	curated
R-HSA-109581	Apoptosis	—
R-HSA-111471	Apoptotic factor-mediated response	—
R-HSA-111461	Cytochrome c-mediated apoptotic response	—
R-HSA-109606	Intrinsic Pathway for Apoptosis	—
R-HSA-1430728	Metabolism	—
R-HSA-71291	Metabolism of amino acids and derivatives	—
R-HSA-1237112	Methionine salvage pathway	electronic
R-HSA-5357801	Programmed Cell Death	—
R-HSA-1614635	Sulfur amino acid metabolism	—

MSigDB gene sets: 173 (showing top): GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_INFLAMMATORY_RESPONSE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, AMIT_EGF_RESPONSE_480_MCF10A, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, MODULE_205, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_METHIONINE_BIOSYNTHETIC_PROCESS, AIYAR_COBRA1_TARGETS_DN, GOBP_METHIONINE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (6): apoptotic process (GO:0006915), negative regulation of apoptotic process (GO:0043066), protein homotetramerization (GO:0051289), pyroptotic inflammatory response (GO:0070269), regulation of ERK1 and ERK2 cascade (GO:0070372), amino acid biosynthetic process (GO:0008652)

GO Molecular Function (6): zinc ion binding (GO:0008270), identical protein binding (GO:0042802), methylthioribulose 1-phosphate dehydratase activity (GO:0046570), protein binding (GO:0005515), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

9 top-level categories:

Category	Pathways
Cytochrome c-mediated apoptotic response	1
Sulfur amino acid metabolism	1
Formation of apoptosome	1
Programmed Cell Death	1
Apoptosis	1
Apoptotic factor-mediated response	1
Intrinsic Pathway for Apoptosis	1
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

22 GO namespaces:

Category	Terms
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
protein homooligomerization	1
protein tetramerization	1
inflammatory response	1
regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
amino acid metabolic process	1
biosynthetic process	1
transition metal ion binding	1
protein binding	1
hydro-lyase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 15 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of apoptotic process	BP	mutant phenotype
protein homotetramerization	BP	direct assay
pyroptotic inflammatory response	BP	mutant phenotype
cytoplasm	CC	direct assay
identical protein binding	MF	physical interaction
methylthioribulose 1-phosphate dehydratase activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,025 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APIP	APAF1	O14727	703
APIP	ENOPH1	Q9UHY7	680
APIP	MRI1	Q9BV20	629
APIP	CASP9	P55211	605
APIP	ADI1	Q9BV57	586
APIP	EHF	Q9NZC4	548
APIP	CYCS	P00001	512
APIP	PDHX	O00330	499
APIP	CASP3	P42574	485
APIP	NAIP	Q13075	483
APIP	PRSS12	P56730	444
APIP	MAN1A1	P33908	430
APIP	NLRP9	Q7RTR0	425
APIP	MTAP	Q13126	419
APIP	GNPDA1	P46926	410

IntAct

Human interaction partners of APIP in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

25 partners by confidence:

Partner	Interaction type	MIscore	Records
LNX1	physical association	0.830	11
NUDT18	physical association	0.710	4
NTAQ1	physical association	0.670	5
PDZD4	physical association	0.670	5
TNPO2	physical association	0.670	4
TSC22D4	physical association	0.670	3
SDCBP	physical association	0.560	5
ATG8	physical association	0.560	3
BAZ2B	physical association	0.560	3
CFAP206	physical association	0.560	3
GORASP2	physical association	0.560	3
IMPDH2	physical association	0.560	3
PSMA1	physical association	0.560	3
RRD1	physical association	0.560	3
SKP1	physical association	0.560	3
SMN1	physical association	0.560	3
ZBTB25	physical association	0.560	3
VSIG8	association	0.530	2
NIF3L1	physical association	0.490	2
PPP1CC	physical association	0.370	1
VIM	physical association	0.370	1
VPS25	physical association	0.370	1
ALOX12B	association	0.350	1
TRAF1	physical association	0.000	1
TRAF2	physical association	0.000	1

BioGRID (75 interactions; top human partners by supporting records): APAF1 (Reconstituted Complex; 3 records), DSG4 (Affinity Capture-MS; 3 records), FASTKD2 (Affinity Capture-MS; 3 records), HEPHL1 (Affinity Capture-MS; 3 records), LNX1 (Two-hybrid; 3 records), LYG2 (Affinity Capture-MS; 3 records), UBA3 (Affinity Capture-MS; 3 records), VSIG8 (Affinity Capture-MS; 3 records), ISOC2 (Affinity Capture-MS; 2 records), NUDT18 (Two-hybrid; 2 records), TSC22D4 (Two-hybrid; 2 records), ALOX12B (Affinity Capture-MS), ARL4C (Affinity Capture-MS), BAZ2B (Two-hybrid), C6orf165 (Two-hybrid)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
APIP	down-regulates	APAF1	binding

Disease & clinical

Genetic variants

Variant evidence for APIP: 62 ClinVar records (0 pathogenic / likely pathogenic); 12 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	5
Benign	10

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 884):

Position(s)	Effect	Δscore	Sites
11:34883505–34883506	acceptor_loss	1.0000	5
11:34888870–34888871	acceptor_loss	1.0000	3
11:34888874–34888876	acceptor_gain	1.0000	2
11:34916226–34916227	donor_loss	1.0000	5
11:34882817–34882818	acceptor_loss	0.9900	6
11:34883505	acceptor_loss	0.9900
11:34888304	donor_gain	0.9900
11:34888870–34888871	acceptor_loss	0.9900	2
11:34888872	acceptor_gain	0.9900
11:34890502–34890503	donor_loss	0.9900	5

AlphaMissense

755 missense substitutions predicted likely pathogenic (of 1,590 scored), across 172 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M140	9	0.970	0.994
H195	8	0.998	0.999
H115	8	0.997	1.000
H117	8	0.996	0.999
N166	8	0.995	0.999
F101	8	0.977	0.997
S95	8	0.934	0.997
D215	8	0.930	0.988
F133	8	0.909	0.997
F218	8	0.907	0.977
D72	8	0.874	0.979
M210	8	0.823	0.931
C97	7	0.994	0.999
W200	7	0.994	0.999
E170	7	0.992	0.997
E139	7	0.987	0.997
K65	7	0.985	0.999
E212	7	0.985	0.994
F74	7	0.984	0.997
W40	7	0.980	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	9.24e-07

Disease associations

OMIM: gene MIM:612491 | disease phenotypes:

GWAS associations

12 associations:

Study	Trait	p-value
GCST003143_16	Lung disease severity in cystic fibrosis	2e-10
GCST004093_36	Prostate-specific antigen levels	2e-10
GCST001077_1	Cystic fibrosis severity	1e-9
GCST003143_12	Lung disease severity in cystic fibrosis	1e-9
GCST006019_35	Gamma glutamyl transferase levels	1e-9
GCST003143_13	Lung disease severity in cystic fibrosis	3e-9
GCST001737_12	Chronic obstructive pulmonary disease-related biomarkers	7e-9
GCST003143_11	Lung disease severity in cystic fibrosis	7e-9
GCST011349_34	Gamma glutamyl transferase levels	2e-8
GCST003143_14	Lung disease severity in cystic fibrosis	1e-7
GCST003143_15	Lung disease severity in cystic fibrosis	3e-6
GCST004867_19	Systemic lupus erythematosus	4e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0005080	CC16 measurement
EFO:0007744	lung disease severity measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation	3
sodium arsenite	decreases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
bismuth tripotassium dicitrate	increases expression	1
bisphenol A	increases expression	1
cobaltous chloride	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1
Cadmium	increases abundance, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Dihydrotestosterone	increases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Particulate Matter	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1708	SNU-C1	Cancer cell line	Male
CVCL_C9G9	SNU-C1/Cas9-hyg	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.