ALAD

Summary

ALAD (aminolevulinate dehydratase, HGNC:395) is a protein-coding gene on chromosome 9q32, encoding Delta-aminolevulinic acid dehydratase (P13716). Catalyzes an early step in the biosynthesis of tetrapyrroles.

The ALAD enzyme is composed of 8 identical subunits and catalyzes the condensation of 2 molecules of delta-aminolevulinate to form porphobilinogen (a precursor of heme, cytochromes and other hemoproteins). ALAD catalyzes the second step in the porphyrin and heme biosynthetic pathway; zinc is essential for enzymatic activity. ALAD enzymatic activity is inhibited by lead and a defect in the ALAD structural gene can cause increased sensitivity to lead poisoning and acute hepatic porphyria. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 210 — RefSeq curated summary.

At a glance

• Gene–disease (curated): porphyria due to ALA dehydratase deficiency (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 219 total — 3 pathogenic, 3 likely-pathogenic
• GTEx eGene: eQTL in 39 tissues, sQTL in 27 (q < 0.05)
• Phenotypes (HPO): 54
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.10 (LoF-tolerant), LOEUF 0.63 (unconstrained)
• MANE Select transcript: NM_000031

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:395
Approved symbol	ALAD
Name	aminolevulinate dehydratase
Location	9q32
Locus type	gene with protein product
Status	Approved
Aliases	ALADH, PBGS
Ensembl gene	ENSG00000148218
Ensembl biotype	protein_coding
OMIM	125270
Entrez	210

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 51 protein_coding, 20 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000409155

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 2, TSL 4: 3, TSL 5: 1

ENST00000409155, ENST00000445750, ENST00000448137, ENST00000452726, ENST00000464749, ENST00000468504, ENST00000482001, ENST00000482847, ENST00000494848, ENST00000907358, ENST00000907359, ENST00000907360, ENST00000907361, ENST00000907362, ENST00000907363, ENST00000907364, ENST00000907365, ENST00000907366, ENST00000907367, ENST00000907368, ENST00000907369, ENST00000907370, ENST00000907371, ENST00000907372, ENST00000907373, ENST00000907374, ENST00000907375, ENST00000907376, ENST00000907377, ENST00000907378, ENST00000907379, ENST00000907380, ENST00000907381, ENST00000907382, ENST00000907383, ENST00000907384, ENST00000907385, ENST00000907386, ENST00000907387, ENST00000907388, ENST00000907389, ENST00000907390, ENST00000907391, ENST00000907392, ENST00000907393, ENST00000907394, ENST00000954349, ENST00000954350, ENST00000954351, ENST00000954352, ENST00000954353, ENST00000954354, ENST00000954355, ENST00000977965, ENST00000977966, ENST00000977967, ENST00000977969, ENST00000977971, ENST00000977972, ENST00000977973, ENST00000977974, ENST00000977975, ENST00000977979, ENST00000977982, ENST00000977983, ENST00000977984, ENST00001010102, ENST00001010105, ENST00001010107, ENST00001010109, ENST00001010111, ENST00001010112, ENST00001010113, ENST00001106898, ENST00001106899, ENST00001140608

RefSeq mRNA: 3 — MANE Select: NM_000031 NM_000031, NM_001003945, NM_001317745

CCDS: CCDS6794

Canonical transcript exons

ENST00000409155 — 12 exons

Exon	Start	End
ENSE00001878459	113386312	113388361
ENSE00001887546	113401212	113401284
ENSE00003458775	113388977	113389106
ENSE00003486374	113389599	113389686
ENSE00003508566	113390593	113390676
ENSE00003526852	113390405	113390493
ENSE00003539748	113390798	113390933
ENSE00003542680	113389438	113389524
ENSE00003550617	113391527	113391623
ENSE00003563403	113393447	113393634
ENSE00003601973	113389773	113389828
ENSE00003630318	113392119	113392169

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.9831 / max 478.4037, expressed in 1797 samples.

Highest expression (Bgee): adrenal gland, adrenal gland cortex, adrenal cortex, C1 segment of cervical spinal cord, inferior olivary complex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ALAD is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 39 tissues and its splicing (sQTL) in 27 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 66 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	sqtl	7.5e-111	-2.27	9:113389221:T:C
Adipose Subcutaneous	sqtl	5.3e-59	-2.26	9:113389221:T:C
Esophagus Mucosa	sqtl	4.5e-57	-2.13	9:113389221:T:C
Skin Not Sun Exposed Suprapubic	sqtl	2.9e-52	-2.01	9:113389221:T:C
Liver	sqtl	8.6e-42	-2.63	9:113389221:T:C
Brain Cerebellum	eqtl	4.5e-37	+1.29	9:113390710:C:G
Thyroid	eqtl	6.1e-37	+0.57	9:113390710:C:G
Muscle Skeletal	eqtl	2.2e-35	-0.54	9:113390710:C:G
Lung	sqtl	3.9e-30	-1.71	9:113389221:T:C
Heart Left Ventricle	eqtl	8.0e-29	+0.25	9:113346040:C:T
Pancreas	sqtl	2.2e-27	-2.33	9:113389221:T:C
Nerve Tibial	eqtl	2.3e-27	-0.45	9:113390710:C:G
Nerve Tibial	sqtl	2.2e-26	-1.65	9:113389221:T:C
Artery Tibial	eqtl	2.2e-26	+0.32	9:113401365:G:C
Esophagus Muscularis	eqtl	2.4e-26	+0.37	9:113386350:C:T
Cells Cultured fibroblasts	eqtl	4.1e-24	-0.47	9:113390710:C:G
Adipose Visceral Omentum	eqtl	1.3e-23	+0.31	9:113385619:C:T
Heart Atrial Appendage	eqtl	3.3e-23	+0.36	9:113346040:C:T
Brain Cerebellar Hemisphere	eqtl	4.4e-23	+1.17	9:113390710:C:G
Adipose Visceral Omentum	sqtl	1.5e-21	-1.67	9:113389221:T:C

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
102103	20.8287	1797
102101	0.0922	13
102100	0.0408	6
102102	0.0215	3

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	98.87	gold quality
right adrenal gland cortex	UBERON:0035827	98.82	gold quality
left adrenal gland	UBERON:0001234	98.53	gold quality
left adrenal gland cortex	UBERON:0035825	98.44	gold quality
adrenal cortex	UBERON:0001235	98.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.14	gold quality
inferior olivary complex	UBERON:0002127	97.54	gold quality
adrenal gland	UBERON:0002369	97.48	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.37	gold quality
spinal cord	UBERON:0002240	97.34	gold quality
parotid gland	UBERON:0001831	97.22	gold quality
trabecular bone tissue	UBERON:0002483	96.32	gold quality
right lobe of liver	UBERON:0001114	96.27	gold quality
substantia nigra	UBERON:0002038	96.11	gold quality
liver	UBERON:0002107	96.04	gold quality
midbrain	UBERON:0001891	95.65	gold quality
medial globus pallidus	UBERON:0002477	95.60	gold quality
amygdala	UBERON:0001876	95.47	gold quality
hypothalamus	UBERON:0001898	95.45	gold quality
body of pancreas	UBERON:0001150	95.43	gold quality
putamen	UBERON:0001874	95.41	gold quality
caudate nucleus	UBERON:0001873	95.28	gold quality
nucleus accumbens	UBERON:0001882	95.19	gold quality
body of stomach	UBERON:0001161	95.16	gold quality
globus pallidus	UBERON:0001875	95.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.76	gold quality
cerebellar hemisphere	UBERON:0002245	94.57	gold quality
apex of heart	UBERON:0002098	94.51	gold quality
heart left ventricle	UBERON:0002084	94.47	gold quality
cerebellar cortex	UBERON:0002129	94.44	gold quality
right frontal lobe	UBERON:0002810	94.43	gold quality
cardiac ventricle	UBERON:0002082	94.35	gold quality
tibial nerve	UBERON:0001323	94.22	gold quality
Ammon’s horn	UBERON:0001954	93.88	gold quality
subthalamic nucleus	UBERON:0001906	93.76	gold quality
gall bladder	UBERON:0002110	93.65	gold quality
heart right ventricle	UBERON:0002080	93.60	gold quality
cingulate cortex	UBERON:0003027	93.52	gold quality
stomach	UBERON:0000945	93.49	gold quality
cerebellum	UBERON:0002037	93.44	gold quality
medulla oblongata	UBERON:0001896	93.43	gold quality
anterior cingulate cortex	UBERON:0009835	93.40	gold quality
esophagus mucosa	UBERON:0002469	93.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.87	gold quality
pons	UBERON:0000988	92.80	gold quality
saliva-secreting gland	UBERON:0001044	92.80	gold quality
central nervous system	UBERON:0001017	92.74	gold quality
prefrontal cortex	UBERON:0000451	92.73	gold quality
mucosa of transverse colon	UBERON:0004991	92.64	gold quality
telencephalon	UBERON:0001893	92.60	gold quality
brain	UBERON:0000955	92.59	gold quality
inferior vagus X ganglion	UBERON:0005363	92.58	gold quality
left ovary	UBERON:0002119	92.53	gold quality
bone marrow	UBERON:0002371	92.46	gold quality
forebrain	UBERON:0001890	92.45	gold quality
fundus of stomach	UBERON:0001160	92.40	gold quality
pancreas	UBERON:0001264	92.40	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.30	gold quality
temporal lobe	UBERON:0001871	92.20	gold quality
adult mammalian kidney	UBERON:0000082	92.15	gold quality
lateral globus pallidus	UBERON:0002476	92.15	gold quality
heart	UBERON:0000948	92.07	gold quality
skin of abdomen	UBERON:0001416	92.07	gold quality
transverse colon	UBERON:0001157	92.05	gold quality
skin of leg	UBERON:0001511	91.85	gold quality
bone marrow cell	CL:0002092	91.83	gold quality
superior vestibular nucleus	UBERON:0007227	91.77	gold quality
metanephros cortex	UBERON:0010533	91.70	gold quality
rectum	UBERON:0001052	91.68	gold quality
cerebral cortex	UBERON:0000956	91.58	gold quality
minor salivary gland	UBERON:0001830	91.58	gold quality
neocortex	UBERON:0001950	91.50	gold quality
descending thoracic aorta	UBERON:0002345	91.50	gold quality
dorsal plus ventral thalamus	UBERON:0001897	91.47	gold quality
right ovary	UBERON:0002118	91.46	gold quality
frontal cortex	UBERON:0001870	91.45	gold quality
ventral tegmental area	UBERON:0002691	91.36	gold quality
right lobe of thyroid gland	UBERON:0001119	91.34	gold quality
cranial nerve II	UBERON:0000941	91.32	gold quality
left ventricle myocardium	UBERON:0006566	91.32	gold quality
zone of skin	UBERON:0000014	91.28	gold quality
lower esophagus mucosa	UBERON:0035834	91.18	gold quality
esophagus	UBERON:0001043	91.10	gold quality
mouth mucosa	UBERON:0003729	91.07	gold quality
kidney	UBERON:0002113	91.04	gold quality
germinal epithelium of ovary	UBERON:0001304	90.99	gold quality
right coronary artery	UBERON:0001625	90.96	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.96	gold quality
adipose tissue	UBERON:0001013	90.90	gold quality
left lobe of thyroid gland	UBERON:0001120	90.77	gold quality
corpus callosum	UBERON:0002336	90.74	gold quality
right atrium auricular region	UBERON:0006631	90.72	gold quality
nephron tubule	UBERON:0001231	90.57	gold quality
connective tissue	UBERON:0002384	90.57	gold quality
thyroid gland	UBERON:0002046	90.51	gold quality
postcentral gyrus	UBERON:0002581	90.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.40	gold quality
substantia nigra pars compacta	UBERON:0001965	90.38	gold quality
monocyte	CL:0000576	90.35	gold quality
adrenal tissue	UBERON:0018303	90.33	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	55.61
E-MTAB-10042	yes	29.62
E-MTAB-9388	yes	9.51
E-ANND-3	yes	8.60
E-HCAD-10	no	2.20

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	196.1	medium
Adrenal gland	tissue	108.7	high
Salivary gland	tissue	92.9	high
Bone marrow	tissue	77.5	low
Locus coeruleus	tissue	72.2
Parathyroid gland	tissue	68.8	medium
Kidney	tissue	68.5	high
Hippocampus	tissue	62.6	low
Nucleus accumbens	tissue	60.7
Adipose tissue	tissue	51.3	low
Heart muscle	tissue	43.8	not detected
Pancreas	tissue	42.3	medium
Postcentral gyrus	tissue	41.5
Stomach 1	tissue	40.4	medium
Choroid plexus	tissue	39.7
Skin 1	tissue	36.8	low
Ovary	tissue	34.6	not detected
Prostate	tissue	32.0	medium
Frontal cortex	tissue	29.2
Esophagus	tissue	28.0	not detected
Duodenum	tissue	27.7	low
Caudate putamen	tissue	27.4
Skeletal muscle	tissue	26.9	not detected
Gallbladder	tissue	25.7	medium
Epididymis	tissue	25.1	low
Small intestine	tissue	25.1	low
Thyroid gland	tissue	24.2	low
Colon	tissue	24.1	low
Placenta	tissue	23.4	low
Rectum	tissue	23.0	low
Seminal vesicle	tissue	22.8	not detected
Tongue	tissue	22.3
Breast	tissue	21.7	low
Spinal cord	tissue	20.3
Lung	tissue	19.4	not detected
Vagina	tissue	19.3	not detected
Thymus	tissue	18.9
Retina	tissue	17.6
Tonsil	tissue	17.5	not detected
Cervix	tissue	17.3	not detected
Smooth muscle	tissue	16.4	not detected
Pituitary gland	tissue	16.3
Appendix	tissue	15.7	not detected
Urinary bladder	tissue	15.3	low
Fallopian tube	tissue	14.7	not detected
Lymph node	tissue	14.6	not detected
Midbrain	tissue	14.6
Medulla oblongata	tissue	14.2
Thalamus	tissue	14.0
Endometrium 1	tissue	13.5	not detected
Spleen	tissue	12.8	not detected
Testis	tissue	12.2	high
Pons	tissue	12.0
Substantia nigra	tissue	11.9
Superior colliculi	tissue	11.7
Cerebral cortex	tissue	11.1	low
Somatosensory cortex	tissue	11.1
Occipital cortex	tissue	10.1
Motor cortex	tissue	9.9
Hypothalamus	tissue	9.9

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Inferior olive (106.7), Medial olivary nucleus (104.3), Red nucleus (102.1), Posterior thalamic nucleus (100.0), Globus pallidus, externus (99.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA

miRNA regulators (miRDB)

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

showing 30 of 50 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4796-5P	99.34	70.06	810
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-7977	98.65	66.18	2590

Functional genomics

gnomAD constraint: pLI 0.0976, LOEUF 0.63, missense Z 2.43 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000409155 — one region, missense o/e 0.72. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mechanistic based studies of porphobilinogen synthase with a proposed reaction intermediate analogue inhibitor suggest that the enzyme can be used as a drug target for the treatment of human microbial and parasitic infections. (PMID:11444968)
• Species-specific inhibition of porphobilinogen synthase by 4-oxosebacic acid (PMID:11909869)
• CYP2E1 overexpression up-regulates both this enzyme and heme oxygenase-1 in a human hepatoma cell line. (PMID:12469218)
• The genetic susceptibility of ALAD polymorphism to lead toxicity may exhibit in a lead dose-dependent manner. (PMID:14694653)
• A cross-sectional evaluation of differences of hematologic parameters by ALAD genotype in male lead workers from Korea. (PMID:15064157)
• Finds no association of animolevulinic acid dehydratase polymorphisms with patella lead concentrations in lead workers. (PMID:15213514)
• ALAD polymorphisms not found to be associated with levels of blood lead and blood zinc protoporphyrin in lead workers (PMID:15258767)
• The Porphobilinogen synthase (PBGS) catalyzes the first common reaction in the biosynthesis of the tetrapyrroles, the asymmetric condensation of two molecules of delta-aminolevulinic acid to form porphobilinogen (PMID:15381398)
• Octameric and hexameric morpheeins of PBGS are very close in energy. Also, W19A assembles into a mixture of dimers, which appear to be stable. (PMID:16377642)
• significant interethnic differences in the distribution of G177C ALAD variants found in the Brazilian population is consistent with differences previously reported in other countries (PMID:16445899)
• Homozygote Rsa and Rsa39488 ALAD 2-2 seems to offer some protection against the effect of lead on motor dexterity function. (PMID:16730797)
• Results point out that there is a correlation among diabetes, hypothyroidism and delta-ALA-D activity. (PMID:17291479)
• A negative correlation was found between the alteration in delta-ALA-D activity and oxidative stress (PMID:17383846)
• study found that ALAD polymorphism had a small or only modest effect on blood lead levels in Thai workers who were exposed to lead (PMID:17649958)
• ALAD 1-1 carriers exhibit a greater likelihood than ALAD 1-2/2-2 carriers of psychiatric symptoms at a higher lead burden. (PMID:17823382)
• certain ALAD genotypes may affect the susceptibility of humans to lead (PMID:17966070)
• The morpheein equilibria of wild type (WT) human PBGS are found to respond to changes in pH, PBGS concentration, and substrate turnover. (PMID:18271513)
• Pregnancy is associated with increased plasma lead/whole blood lead ratio in ALAD 1-1 genotype. (PMID:18282196)
• A significant difference was seen in the frequency distribution of ALAD genotype between Uygur and Han races. The genetic susceptibility of ALAD polymorphism to lead toxicity may exhibit in a lead dose-dependent manner. (PMID:18795909)
• ALAD G177C polymorphism along with BLL and assessment of hematological parameters may play an important role in evaluation and better understanding of the consequences of lead exposure. (PMID:19028776)
• genotype was significantly associated with the blood lead concentration (PMID:19440429)
• Polymorphisms of ALAD and VDR gene may play an important role in lead nephrotoxicity in high lead-exposed workers. (PMID:19548578)
• The frequencies of ALAD2 in Asian populations were comparable to those in Caucasians, while Africans had no mutation allele (PMID:19766174)
• ALAD has a major and limiting role in regulating protoporphyrin IX synthesis and photodynamic therapy outcome. (PMID:19789817)
• Allosteric inhibition of human porphobilinogen synthase. (PMID:19812033)
• blood lead levels may be an important risk factor for hypertension and increased systolic and diastolic blood pressure. These associations may be modified by ALAD genotype. (PMID:20123609)
• Lead-exposed workers with the ALAD2 allele appear to be more susceptible to the effects of lead on renal injury, whereas neurobehavioral functions in ALAD1 homozygote tend to be more vulnerable. (PMID:20510440)
• Examined whether the ALAD G177C single nucleotide polymorphism (SNP) affects the relationship between lead and mortality; observed no convincing interaction effect between ALAD genotype and blood lead level on mortality risk. (PMID:21293208)
• ALAD2 and hPEPT2*2 polymorphisms may exaggerate Pb blood burden in boys. (PMID:21327641)
• Study suggests that the lead-exposure-induced increases in ALAD methylation may be involved in the mechanism of lead toxicity. (PMID:21396434)
• ALAD genotype modifies the relationship between Pb and its toxic effects on the peripheral nervous system. This must be considered in the assessment of risks at Pb exposure. (PMID:21439310)
• association between oxidative stress, abnormalities on lipid profile, distribution of body fat and delta-ALA-D activity inhibition; the enzyme is more oxidized in the DM2 patient (PMID:21762684)
• A common genetic variation in ALAD may alter the risk of renal cell carcinoma (PMID:21799727)
• This study demonostrated that modification by the genes ALAD lead-induced cognitive effects in children. (PMID:22101007)
• distribution of a single nucleotide polymorphism in two populations from the Iberian Peninsula (PMID:22298357)
• Workers with the ALAD 1-1 genotype were associated with higher blood lead levels than those with the ALAD 1-2 genotype. (PMID:22851944)
• The results lend support to the notion that ALAD polymorphism exerts no marked impact on lead body burden. (PMID:24156693)
• Genetic variation in ALAD may modify associations between Pb and prostate cancer (PMID:24500903)
• Report the effect of ALAD polymorphism on hematopoietic, hepatic and renal toxicity from lead in occupational exposure workers. (PMID:24631795)
• This study investigated the delta-aminolevulinate dehydratase (delta-ALA-D) activity in whole blood as well as the parameters of oxidative stress, in lung cancer. (PMID:24855033)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	alad	ENSDARG00000100372
mus_musculus	Alad	ENSMUSG00000028393
rattus_norvegicus	Alad	ENSRNOG00000015206
drosophila_melanogaster	Pbgs	FBGN0036271

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96853) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 13 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal sternum morphology	1
abnormal liver morphology	1
enlarged lymph nodes	1
enlarged thymus	1
increased circulating triglyceride level	1
abnormal seminal vesicle morphology	1
abnormal skin morphology	1
small adrenal glands	1
decreased red blood cell distribution width	1
preweaning lethality, complete penetrance	1
enlarged urinary bladder	1
embryonic lethality prior to organogenesis	1
prenatal lethality prior to heart atrial septation	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
Escherichia coli K-12	P0ACB2	100.0%	Diamond
Shigella flexneri	P0ACB3	100.0%	Diamond
Staphylococcus aureus subsp. aureus Mu50	P64333	100.0%	Diamond
Staphylococcus aureus subsp. aureus N315	P64334	100.0%	Diamond
Staphylococcus aureus subsp. aureus MW2	P64335	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WMP4	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WMP5	100.0%	Diamond
Staphylococcus aureus subsp. aureus NCTC 8325	Q2FXR3	100.0%	Diamond
Staphylococcus aureus subsp. aureus COL	Q5HFA4	100.0%	Diamond
Staphylococcus epidermidis RP62A	Q5HNN5	100.0%	Diamond
Staphylococcus aureus subsp. aureus MSSA476	Q6G8Q7	100.0%	Diamond
Staphylococcus aureus subsp. aureus MRSA252	Q6GG37	100.0%	Diamond
Staphylococcus epidermidis ATCC 12228	Q8CNZ0	100.0%	Diamond
Staphylococcus aureus	P0C1R9	99.4%	Diamond
Pongo abelii	Q5R971	98.2%	Diamond
Macaca fascicularis	Q60HH9	97.9%	Diamond
Chlorobaculum parvum NCIB 8327	Q59334	97.3%	Diamond
Chlorobaculum tepidum TLS	Q8KCJ0	97.3%	Diamond
Helicobacter pylori 26695	P56074	96.3%	Diamond
Helicobacter pylori J99	Q9ZMR8	96.3%	Diamond
Bos taurus	Q58DK5	93.0%	Diamond
Hordeum vulgare	Q42836	89.4%	Diamond
Oryza sativa Japonica Group	Q5Z8V9	89.4%	Diamond
Mycobacterium leprae TN	P46723	87.8%	Diamond
Saccharomyces cerevisiae S288C	P05373	87.3%	Diamond
Lathyrus oleraceus	P30124	87.1%	Diamond
Nakaseomyces glabratus CBS 138	O42768	86.8%	Diamond
Chlamydia trachomatis D/UW-3/CX	O84638	86.8%	Diamond
Chlamydia muridarum str. Nigg	Q9PLU4	86.8%	Diamond
Spinacia oleracea	P24493	84.3%	Diamond
Selaginella martensii	P45623	84.2%	Diamond
Physcomitrium patens	Q43058	84.2%	Diamond
Glycine max	P43210	83.6%	Diamond
Arabidopsis thaliana	Q9SFH9	83.3%	Diamond
Synechococcus elongatus PCC 7942 = FACHB-805	P43087	83.1%	Diamond
Synechocystis sp. PCC 6803 substr. Kazusa	P77969	83.1%	Diamond
Eremothecium gossypii ATCC 10895	Q750E0	83.1%	Diamond
Bacillus subtilis subsp. subtilis str. 168	P30950	69.5%	Diamond
Halalkalibacterium halodurans C-125	Q9K8G2	69.5%	Diamond
Streptomyces coelicolor A3(2)	P54919	65.7%	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
C9orf43	protein-coding	257169
POLE3	protein-coding	54107
RGS3	protein-coding	5998
HDHD3	protein-coding	81932
WDR31	protein-coding	114987
RNF183	protein-coding	138065
BSPRY	protein-coding	54836

Protein

Protein identifiers

Delta-aminolevulinic acid dehydratase — P13716 (reviewed: P13716)

Alternative names: Porphobilinogen synthase

All UniProt accessions (6): A0A140VJL9, B7Z3I9, P13716, B7ZBK6, B7ZBK7, B7ZBK8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen.

Subunit / interactions. Homooctamer; active form. Homohexamer; low activity form.

Subcellular location. Cytoplasm. Cytosol.

Disease relevance. Acute hepatic porphyria (AHEPP) [MIM:612740] A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. AHP is characterized by attacks of gastrointestinal disturbances, abdominal colic, paralyses and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Can alternate between a fully active homooctamer and a low-activity homohexamer. A bound magnesium ion may promote the assembly of the fully active homooctamer. The magnesium-binding site is absent in the low-activity homohexamer. Inhibited by compounds that favor the hexameric state. Inhibited by divalent lead ions. The lead ions partially displace the zinc cofactor.

Cofactor. Binds 8 zinc ions per octamer. Requires four zinc ions per octamer for full catalytic activity. Can bind up to 2 zinc ions per subunit.

Pathway. Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; coproporphyrinogen-III from 5-aminolevulinate: step 1/4.

Polymorphism. Genetic variation in ALAD influences susceptibility to lead poisoning in individuals exposed to high amount of environmental lead. There are two common alleles: allele ALAD1 and allele ALAD2 resulting in 3 isozymes: ALAD 1-1, ALAD 1-2, and ALAD 2-2. Individuals with ALAD 1-2 or ALAD 2-2 isozymes have levels of blood lead higher than those in individuals with ALAD 1-1 isozyme. The sequence shown corresponds to allele ALAD*1.

Similarity. Belongs to the ALAD family.

Isoforms (2)

UniProt ID	Names	Canonical?
P13716-1	1	yes
P13716-2	2

RefSeq proteins (3): NP_000022, NP_001003945, NP_001304674 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001731	ALAD	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR030656	ALAD_AS	Active_site

Pfam: PF00490

Enzyme classification (BRENDA)

• EC 4.2.1.24 — porphobilinogen synthase (BRENDA: 79 organisms, 25 substrates, 198 inhibitors, 37 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
5-AMINOLEVULINATE	0.043–2	26
5-AMINOLEVULINIC ACID	0.0003–18	10

Catalyzed reactions (Rhea)

• 2 5-aminolevulinate = porphobilinogen + 2 H2O + H(+) (RHEA:24064)

UniProt features (68 total): strand 19, helix 17, binding site 9, sequence variant 7, mutagenesis site 5, turn 4, modified residue 3, active site 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
1PV8	Crystal structure of a low activity F12L mutant of human porphobilinogen synthase	X-RAY DIFFRACTION	2.2
5HMS	X-ray structure of human recombinant 5-aminolaevulinic acid dehydratase (hrALAD).	X-RAY DIFFRACTION	2.8
1E51	Crystal structure of native human erythrocyte 5-aminolaevulinic acid dehydratase	X-RAY DIFFRACTION	2.83
5HNR	The X-ray structure of octameric human native 5-aminolaevulinic acid dehydratase.	X-RAY DIFFRACTION	2.83

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13716-F1	96.34	0.94

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Lyases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of cofactor/vitamin metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH enhanced · 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 (2)

Position	Role
199	schiff-base intermediate with substrate
252	schiff-base intermediate with substrate

Ligand- & substrate-binding residues (9)

Position	Role
279	5-aminolevulinate
318	5-aminolevulinate
122	Zn(2+)
124	Zn(2+)
131	Zn(2+)
132	Zn(2+)
209	5-aminolevulinate
221	5-aminolevulinate
223	Zn(2+)

Post-translational modifications (3)

Type	Positions
N6-succinyllysine	199, 252
Phosphoserine	215

Mutagenesis-validated functional residues (5)

Position	Phenotype
122	reduces enzyme activity about 1000000-fold; when associated with a-124 and a-132.
124	reduces enzyme activity about 1000000-fold; when associated with a-122 and a-132.
131	no effect on catalytic activity; when associated with a-223.
132	reduces enzyme activity about 1000000-fold; when associated with a-122 and a-124.
223	no effect on catalytic activity; when associated with a-131.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-189451	Heme biosynthesis	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-1430728	Metabolism	—
R-HSA-189445	Metabolism of porphyrins	—

MSigDB gene sets: 391 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ZINC_ION, GNF2_PRDX2, YANG_BREAST_CANCER_ESR1_LASER_UP, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_INTERLEUKIN_4, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_RESPONSE_TO_CORTICOSTEROID, REACTOME_METABOLISM_OF_PORPHYRINS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN

GO Biological Process (38): response to hypoxia (GO:0001666), heme biosynthetic process (GO:0006783), heme A biosynthetic process (GO:0006784), heme B biosynthetic process (GO:0006785), response to oxidative stress (GO:0006979), response to xenobiotic stimulus (GO:0009410), response to herbicide (GO:0009635), response to iron ion (GO:0010039), response to zinc ion (GO:0010043), response to aluminum ion (GO:0010044), response to ionizing radiation (GO:0010212), response to vitamin B1 (GO:0010266), response to selenium ion (GO:0010269), response to activity (GO:0014823), response to cobalt ion (GO:0032025), response to lipopolysaccharide (GO:0032496), response to vitamin E (GO:0033197), response to amino acid (GO:0043200), response to ethanol (GO:0045471), response to arsenic-containing substance (GO:0046685), response to cadmium ion (GO:0046686), response to mercury ion (GO:0046689), protein homooligomerization (GO:0051260), response to glucocorticoid (GO:0051384), response to methylmercury (GO:0051597), response to platinum ion (GO:0070541), response to fatty acid (GO:0070542), cellular response to lead ion (GO:0071284), negative regulation of proteasomal protein catabolic process (GO:1901799), porphyrin-containing compound biosynthetic process (GO:0006779), response to nutrient (GO:0007584), response to toxic substance (GO:0009636), response to hormone (GO:0009725), response to metal ion (GO:0010038), response to lead ion (GO:0010288), response to nutrient levels (GO:0031667), tetrapyrrole biosynthetic process (GO:0033014), response to vitamin (GO:0033273)

GO Molecular Function (8): catalytic activity (GO:0003824), porphobilinogen synthase activity (GO:0004655), zinc ion binding (GO:0008270), lead ion binding (GO:0032791), identical protein binding (GO:0042802), proteasome core complex binding (GO:1904854), lyase activity (GO:0016829), metal ion binding (GO:0046872)

GO Cellular Component (6): extracellular region (GO:0005576), nucleus (GO:0005634), cytosol (GO:0005829), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Metabolism of porphyrins	1
Innate Immune System	1
Immune System	1
Metabolism	1

GO top-level categories

34 GO namespaces:

Category	Terms
response to metal ion	4
response to stress	3
response to chemical	3
heme biosynthetic process	2
response to vitamin	2
response to alcohol	2
response to oxygen-containing compound	2
cellular anatomical structure	2
response to decreased oxygen levels	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
response to toxic substance	1
response to radiation	1
response to nitrogen compound	1
response to stimulus	1
response to molecule of bacterial origin	1
response to lipid	1
response to acid chemical	1
molecular_function	1
hydro-lyase activity	1
transition metal ion binding	1
metal ion binding	1
protein binding	1
protein-containing complex binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
secretory granule	1
cytoplasmic vesicle lumen	1
extracellular vesicle	1
intracellular organelle lumen	1
ficolin-1-rich granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 54 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
heme B biosynthetic process	BP	direct assay
heme biosynthetic process	BP	direct assay
negative regulation of proteasomal protein catabolic process	BP	direct assay
protein homooligomerization	BP	physical interaction
extracellular exosome	CC	high-throughput assay
nucleus	CC	high-throughput assay
identical protein binding	MF	physical interaction
lead ion binding	MF	experiment
porphobilinogen synthase activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,488 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALAD	CPOX	P36551	967
ALAD	HMBS	P08396	965
ALAD	UROD	P06132	955
ALAD	UROS	P10746	906
ALAD	FECH	P22830	868
ALAD	PPOX	P50336	862
ALAD	ALAS1	P13196	790
ALAD	ALAS2	P22557	749
ALAD	ACO1	P21399	698
ALAD	AK1	P00568	670
ALAD	PGM3	O95394	619
ALAD	HAMP	P81172	587
ALAD	EARS2	Q5JPH6	586
ALAD	GATA1	P15976	577
ALAD	ABCB6	Q9NP58	562

IntAct

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

2 partners by confidence:

Partner	Interaction type	MIscore	Records
RASGRP2	physical association	0.400	1
HUNK	physical association	0.000	1

BioGRID (56 interactions; top human partners by supporting records): ARHGEF35 (Affinity Capture-MS; 2 records), CNN2 (Affinity Capture-MS; 2 records), ISOC2 (Affinity Capture-MS; 2 records), PRNP (Affinity Capture-MS; 2 records), ACTR2 (Co-fractionation), ADRBK1 (Negative Genetic), AGFG1 (Co-fractionation), ANKRD22 (Affinity Capture-MS), ATP6AP2 (Affinity Capture-MS), C14orf142 (Co-fractionation), CARM1 (Positive Genetic), CCDC103 (Affinity Capture-MS), CCNC (Affinity Capture-MS), DBNL (Co-fractionation), DDX58 (Affinity Capture-RNA)

Disease & clinical

Genetic variants

Variant evidence for ALAD: 219 ClinVar records (6 pathogenic / likely pathogenic); 6 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	96
Likely benign	62
Benign	28

Top pathogenic / likely-pathogenic (6)

Showing all 6 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
16862	NM_000031.6(ALAD):c.397G>A (p.Gly133Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	4
1068016	NM_000031.6(ALAD):c.481+1G>T	Likely pathogenic	criteria provided, single submitter	1
3067962	NM_000031.6(ALAD):c.165-2A>G	Likely pathogenic	criteria provided, single submitter	1
16866	NM_000031.6(ALAD):c.820G>A (p.Ala274Thr)	Pathogenic	no assertion criteria provided	1
16868	NM_000031.6(ALAD):c.165-11C>A	Pathogenic	no assertion criteria provided	1
16869	NM_000031.6(ALAD):c.165-11C>T	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ALAD’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 44 predictions of 877):

Position(s)	Effect	Δscore	Sites
9:113388362–113388363	acceptor_loss	1.0000	5
9:113388975–113388976	donor_loss	1.0000	5
9:113389107–113389108	acceptor_loss	1.0000	5
9:113389436–113389437	donor_loss	1.0000	5
9:113389525–113389526	acceptor_loss	1.0000	4
9:113389597–113389598	donor_loss	1.0000	5
9:113389687–113389688	acceptor_loss	1.0000	6
9:113390403–113390404	donor_loss	1.0000	3
9:113390494	acceptor_gain	1.0000
9:113390494–113390495	acceptor_loss	1.0000	5

AlphaMissense

902 missense substitutions predicted likely pathogenic (of 2,131 scored), across 237 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
D120	8	0.988	0.996
F208	8	0.978	0.996
F79	8	0.973	0.997
D241	8	0.967	0.985
F36	8	0.962	0.994
D259	8	0.960	0.985
D169	8	0.956	0.987
H131	8	0.938	0.980
D247	8	0.928	0.969
M170	8	0.893	0.965
D172	8	0.887	0.956
H129	8	0.792	0.904
F200	7	0.980	0.994
C122	7	0.979	0.994
C124	7	0.971	0.992
C132	7	0.968	0.986
E281	7	0.960	0.984
K199	7	0.957	0.997
K252	7	0.954	0.992
F282	7	0.948	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

6 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	4.8e-10
Liver Hepatocellular Carcinoma (validation)	favorable	1.72e-05
Colon Adenocarcinoma (validation)	unfavorable	7.44e-05
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000267
Liver Hepatocellular Carcinoma (TCGA)	favorable	0.000362
Lung Squamous Cell Carcinoma (validation)	favorable	0.000501

Disease associations

OMIM: gene MIM:125270 | disease phenotypes: MIM:612740

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
porphyria due to ALA dehydratase deficiency	Strong	Autosomal recessive	6

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
porphyria due to ALA dehydratase deficiency	Moderate	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (9 panels, 5 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

9 panels:

Panel	Rating
Cutaneous photosensitivity with a likely genetic cause	green
Likely inborn error of metabolism	green
Non-acute porphyrias	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber

Mondo (1): porphyria due to ALA dehydratase deficiency (MONDO:0013000)

Orphanet (2): Porphyria due to ALA dehydratase deficiency (Orphanet:100924), Acute hepatic porphyria (Orphanet:95157)

HPO phenotypes

54 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000707	Abnormality of the nervous system
HP:0000711	Restlessness
HP:0000713	Agitation
HP:0000716	Depression
HP:0000717	Autism
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000763	Sensory neuropathy
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001271	Polyneuropathy
HP:0001288	Gait disturbance
HP:0001289	Confusion
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001878	Hemolytic anemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002086	Abnormality of the respiratory system
HP:0002093	Respiratory insufficiency
HP:0002203	Respiratory paralysis
HP:0002572	Episodic vomiting
HP:0002902	Hyponatremia
HP:0003163	Elevated urinary delta-aminolevulinic acid
HP:0003270	Abdominal distention
HP:0003401	Paresthesia
HP:0003470	Paralysis
HP:0003577	Congenital onset
HP:0003690	Limb muscle weakness
HP:0004302	Functional motor deficit
HP:0005547	Myeloproliferative disorder
HP:0005946	Ventilator dependence with inability to wean
HP:0006466	Ankle flexion contracture
HP:0007159	Fluctuations in consciousness
HP:0007178	Motor polyneuropathy
HP:0009830	Peripheral neuropathy
HP:0010472	Abnormal circulating porphyrin concentration
HP:0011121	Abnormal skin morphology
HP:0011848	Abdominal colic
HP:0012187	Increased erythrocyte protoporphyrin concentration
HP:0012217	Increased urinary porphobilinogen
HP:0012379	Abnormal circulating enzyme concentration or activity
HP:0030272	Abnormal erythrocyte enzyme concentration or activity
HP:0031258	Delirium
HP:0033010	Increased fecal coproporphyrin 3
HP:0040322	Purple urine
HP:0100852	Abnormal fear-induced behavior

GWAS associations

6 associations:

Study	Trait	p-value
GCST90002386_137	High light scatter reticulocyte percentage of red cells	1e-14
GCST002831_1	Lead levels in blood	4e-14
GCST90002385_23	High light scatter reticulocyte count	4e-14
GCST90002406_516	Reticulocyte fraction of red cells	1e-12
GCST90002405_284	Reticulocyte count	9e-12
GCST002831_15	Lead levels in blood	2e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007986	reticulocyte count

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C562618	Porphyria, Acute Hepatic *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3126 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

4 measured of 5 human assays (20 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL2430564	IC50	85300 nM
CHEMBL2430563	IC50	99700 nM
CHEMBL2430571	IC50	119000 nM
CHEMBL2407927	KI	2e+08 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lead	increases response to substance, affects cotreatment, affects reaction, decreases reaction, decreases expression (+4 more)	23
Valproic Acid	decreases expression, increases expression	5
Estradiol	affects cotreatment, increases expression, decreases expression	4
trichostatin A	affects cotreatment, decreases expression, affects expression	3
sodium arsenite	affects expression, decreases expression	3
Cyclosporine	decreases expression	3
bisphenol A	decreases expression	2
Aminolevulinic Acid	increases metabolic processing, affects reaction	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Cadmium	affects cotreatment, affects reaction, decreases activity, decreases reaction	2
Carmustine	decreases expression, affects cotreatment, decreases activity	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Diethylstilbestrol	decreases expression	2
Dithiothreitol	increases activity, increases reaction, affects cotreatment, affects reaction, decreases activity (+1 more)	2
Hydrogen Peroxide	affects expression, increases expression	2
Smoke	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
FR900359	increases phosphorylation	1
acephate	decreases activity	1
glycidyl methacrylate	decreases expression	1
methylselenic acid	increases expression	1
methamidophos	decreases activity	1
afimoxifene	decreases expression, decreases reaction	1
zinc chloride	decreases reaction, increases activity, increases reaction	1
lead nitrate	decreases reaction, increases activity, increases reaction, decreases activity	1
zinc protoporphyrin	affects abundance	1
butyraldehyde	decreases expression	1
bromobenzene	decreases activity	1
triethyllead acetate	decreases reaction, increases activity, increases reaction, decreases activity	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2410324	Binding	Inhibition of ALAD (unknown origin)	Synthesis and in vitro cellular uptake of 11C-labeled 5-aminolevulinic acid derivative to estimate the induced cellular accumulation of protoporphyrin IX. — *Bioorg Med Chem Lett*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2I0	Abcam Raji ALAD KO	Cancer cell line	Male
CVCL_UQ11	Abcam Jurkat ALAD KO	Cancer cell line	Male
CVCL_WQ95	Abcam K-562 ALAD KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

8 trials:

NCT	Phase	Status	Title
NCT03338816	Phase 3	COMPLETED	ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
NCT03505853	Phase 1	COMPLETED	A Study to Investigate the Interaction Between Givosiran and a 5-probe Drug Cocktail in Patients With Acute Intermittent Porphyria (AIP)
NCT02240784	Not specified	COMPLETED	EXPLORE: A Natural History Study of Acute Hepatic Porphyria (AHP)
NCT03547297	Not specified	TERMINATED	INSIGHT-AHP: A Study to Characterize the Prevalence of Acute Hepatic Porphyria (AHP) in Patients With Clinical Presentation and History Consistent With AHP
NCT04056481	Not specified	APPROVED_FOR_MARKETING	Expanded Access Protocol of Givosiran for Patients With Acute Hepatic Porphyria
NCT04883905	Not specified	RECRUITING	ELEVATE, a Registry of Patients With Acute Hepatic Porphyria (AHP)
NCT04923516	Not specified	COMPLETED	Prevalence of Acute Hepatic Porphyria
NCT05344599	Not specified	ACTIVE_NOT_RECRUITING	Evaluating the Prevalence of Acute Hepatic Porphyria in Postural Tachycardia Syndrome

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ALAD across ~30M SureChEMBL compounds — explore on Sugi Predict.