P22557 (HEM0_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
5-aminolevulinate synthase, erythroid-specific, mitochondrial
Short name=ALAS-E
EC=2.3.1.37

Alternative name(s):
5-aminolevulinic acid synthase 2
Delta-ALA synthase 2
Delta-aminolevulinate synthase 2

Gene names

Name:	ALAS2
Synonyms:	ALASE, ASB

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	587 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Catalytic activity	Succinyl-CoA + glycine = 5-aminolevulinate + CoA + CO2.
Cofactor	Pyridoxal phosphate.
Pathway	Porphyrin metabolism; protoporphyrin-IX biosynthesis; 5-aminolevulinate from glycine: step 1/1.
Subunit structure	Homodimer.
Subcellular location	Mitochondrion matrix.
Tissue specificity	Erythroid specific.
Involvement in disease	Defects in ALAS2 are a cause of anemia sideroblastic X-linked (XLSA) [MIM:300751]. Sideroblastic anemia is characterized by anemia of varying severity, hypochromic peripheral erythrocytes, systemic iron overload secondary to chronic ineffective erythropoiesis, and the presence of bone marrow ringed sideroblasts. Sideroblasts are characterized by iron-loaded mitochondria clustered around the nucleus. XLSA shows a variable hematologic response to pharmacologic doses of pyridoxine. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.13 Ref.15 Defects in ALAS2 are the cause of erythropoietic protoporphyria X-linked dominant (XLDPT) [MIM:300752]. 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. XLDPT is a form of porphyria characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease. Note=Gain of function mutations in ALS2 are responsible for XLDPT, but they can also be a possible aggravating factor in congenital erythropoietic porphyria and other erythropoietic disorders caused by mutations in other genes (Ref.15). Ref.12
Miscellaneous	There are two delta-ALA synthases in vertebrates: an erythroid- specific form and one (housekeeping) which is expressed in all tissues.
Sequence similarities	Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.
Sequence caution	The sequence CAA39795.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Heme biosynthesis
Cellular component	Mitochondrion
Disease	Disease mutation
Domain	Transit peptide
Ligand	Pyridoxal phosphate
Molecular function	Acyltransferase Transferase
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cellular iron ion homeostasis Inferred from sequence or structural similarity. Source: UniProtKB erythrocyte differentiation Inferred from sequence or structural similarity. Source: UniProtKB heme biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB hemoglobin biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB oxygen homeostasis Non-traceable author statement. Source: UniProtKB response to hypoxia Inferred from direct assay. Source: UniProtKB
Cellular component	mitochondrial inner membrane Inferred from direct assay. Source: UniProtKB mitochondrial matrix Traceable author statement. Source: Reactome
Molecular function	5-aminolevulinate synthase activity Inferred from direct assay. Source: UniProtKB coenzyme binding Inferred from sequence or structural similarity. Source: UniProtKB glycine binding Inferred from sequence or structural similarity. Source: UniProtKB protein binding Inferred from physical interaction. Source: UniProtKB pyridoxal phosphate binding Inferred from electronic annotation. Source: InterPro transferase activity, transferring nitrogenous groups Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – ?49	49	Mitochondrion
	Chain	?50 – 587	538	5-aminolevulinate synthase, erythroid-specific, mitochondrial		PRO_0000001223
Amino acid modifications
	Modified residue	391	1	N6-(pyridoxal phosphate)lysine Probable
Natural variations
	Natural variant	156	1	K → E in XLSA; significantly reduced activity. Ref.13		VAR_066232
	Natural variant	159	1	D → Y in XLSA. Ref.11		VAR_018604
	Natural variant	170	1	R → H in XLSA; significantly increased thermosensitivity. Ref.15		VAR_066233
	Natural variant	199	1	Y → H in XLSA. Ref.9		VAR_012334
	Natural variant	204	1	R → Q in XLSA; 15% to 35% activity of wild-type. Ref.8		VAR_012335
	Natural variant	218	1	R → H in XLSA; significantly increased thermosensitivity. Ref.15		VAR_066234
	Natural variant	242	1	E → K in XLSA; significantly reduced activity. Ref.15		VAR_066235
	Natural variant	263	1	D → N in XLSA; significantly reduced activity. Ref.15		VAR_066236
	Natural variant	339	1	P → L in XLSA; significantly reduced activity. Ref.15		VAR_066237
	Natural variant	375	1	R → C in XLSA; significantly reduced activity. Ref.15		VAR_066238
	Natural variant	388	1	T → S in XLSA. Ref.5		VAR_000562
	Natural variant	411	1	R → C in XLSA; 12% to 25% activity of wild-type. Ref.7 Ref.9		VAR_000563
	Natural variant	411	1	R → H in XLSA; significantly reduced activity. Ref.15		VAR_066239
	Natural variant	448	1	R → Q in XLSA. Ref.9		VAR_012336
	Natural variant	452	1	R → C in XLSA. Ref.9 Ref.13		VAR_012337
	Natural variant	452	1	R → G in XLSA; does not affect activity. Ref.15		VAR_066240
	Natural variant	452	1	R → H in XLSA. Ref.13		VAR_066241
	Natural variant	476	1	I → N in XLSA. Ref.6		VAR_000564
	Natural variant	520	1	P → L. Ref.15		VAR_066242
	Natural variant	560	1	R → H in XLSA. Ref.10		VAR_018605
	Natural variant	572	1	R → H in XLSA; does not affect activity. Ref.15		VAR_066243
	Natural variant	586	1	Y → F Rare variant found in a congenital erythropoietic porphyria patient that also carries UROS mutations R-73R and Q-248; increased enzyme activity. Ref.14		VAR_066244
Experimental info
	Sequence conflict	182	1	S → F in CAA39795. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P22557 [UniParc]. Last modified January 23, 2002. Version 2. Checksum: FD821BE245C440B5	FASTA	587	64,633
	10 20 30 40 50 60 MVTAAMLLQC CPVLARGPTS LLGKVVKTHQ FLFGIGRCPI LATQGPNCSQ IHLKATKAGG 70 80 90 100 110 120 DSPSWAKGHC PFMLSELQDG KSKIVQKAAP EVQEDVKAFK TDLPSSLVSV SLRKPFSGPQ 130 140 150 160 170 180 EQEQISGKVT HLIQNNMPGN YVFSYDQFFR DKIMEKKQDH TYRVFKTVNR WADAYPFAQH 190 200 210 220 230 240 FSEASVASKD VSVWCSNDYL GMSRHPQVLQ ATQETLQRHG AGAGGTRNIS GTSKFHVELE 250 260 270 280 290 300 QELAELHQKD SALLFSSCFV ANDSTLFTLA KILPGCEIYS DAGNHASMIQ GIRNSGAAKF 310 320 330 340 350 360 VFRHNDPDHL KKLLEKSNPK IPKIVAFETV HSMDGAICPL EELCDVSHQY GALTFVDEVH 370 380 390 400 410 420 AVGLYGSRGA GIGERDGIMH KIDIISGTLG KAFGCVGGYI ASTRDLVDMV RSYAAGFIFT 430 440 450 460 470 480 TSLPPMVLSG ALESVRLLKG EEGQALRRAH QRNVKHMRQL LMDRGLPVIP CPSHIIPIRV 490 500 510 520 530 540 GNAALNSKLC DLLLSKHGIY VQAINYPTVP RGEELLRLAP SPHHSPQMME DFVEKLLLAW 550 560 570 580 TAVGLPLQDV SVAACNFCRR PVHFELMSEW ERSYFGNMGP QYVTTYA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Two different genes encode delta-aminolevulinate synthase in humans: nucleotide sequences of cDNAs for the housekeeping and erythroid genes." Bishop D.F. Nucleic Acids Res. 18:7187-7188(1990) [PubMed: 2263504] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"Human erythroid 5-aminolevulinate synthase: promoter analysis and identification of an iron-responsive element in the mRNA." Cox T.C., Bawden M.J., Martin A., May B.K. EMBO J. 10:1891-1902(1991) [PubMed: 2050125] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[3]	"Identification and characterization of a conserved erythroid-specific enhancer located in intron 8 of the human 5-aminolevulinate synthase 2 gene." Surinya K.H., Cox T.C., May B.K. J. Biol. Chem. 273:16798-16809(1998) [PubMed: 9642238] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed: 15772651] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"X-linked pyridoxine-responsive sideroblastic anemia due to a Thr388-to-Ser substitution in erythroid 5-aminolevulinate synthase." Cox T.C., Bottomley S.S., Wiley J.S., Bawden M.J., Matthews C.S., May B.K. N. Engl. J. Med. 330:675-679(1994) [PubMed: 8107717] [Abstract] Cited for: VARIANT XLSA SER-388.
[6]	"Enzymatic defect in 'X-linked' sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency." Cotter P.D., Baumann M., Bishop D.F. Proc. Natl. Acad. Sci. U.S.A. 89:4028-4032(1992) [PubMed: 1570328] [Abstract] Cited for: VARIANT XLSA ASN-476.
[7]	"R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity." Furuyama K., Uno R., Urabe A., Hayashi N., Fujita H., Kondo M., Sassa S., Yamamoto M. Br. J. Haematol. 103:839-841(1998) [PubMed: 9858242] [Abstract] Cited for: VARIANT XLSA CYS-411.
[8]	"A novel mutation of the erythroid-specific gamma-aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia." Harigae H., Furuyama K., Kudo K., Hayashi N., Yamamoto M., Sassa S., Sasaki T. Am. J. Hematol. 62:112-114(1999) [PubMed: 10577279] [Abstract] Cited for: VARIANT XLSA GLN-204.
[9]	"Four new mutations in the erythroid-specific 5-aminolevulinate synthase (ALAS2) gene causing X-linked sideroblastic anemia: increased pyridoxine responsiveness after removal of iron overload by phlebotomy and coinheritance of hereditary hemochromatosis." Cotter P.D., May A., Li L., Al-Sabah A.I., Fitzsimons E.J., Cazzola M., Bishop D.F. Blood 93:1757-1769(1999) [PubMed: 10029606] [Abstract] Cited for: VARIANTS XLSA HIS-199; CYS-411; GLN-448 AND CYS-452.
[10]	"Absent phenotypic expression of X-linked sideroblastic anemia in one of 2 brothers with a novel ALAS2 mutation." Cazzola M., May A., Bergamaschi G., Cerani P., Ferrillo S., Bishop D.F. Blood 100:4236-4238(2002) [PubMed: 12393718] [Abstract] Cited for: VARIANT XLSA HIS-560.
[11]	"A novel mutation in exon 5 of the ALAS2 gene results in X-linked sideroblastic anemia." Hurford M.T., Marshall-Taylor C., Vicki S.L., Zhou J.Z., Silverman L.M., Rezuke W.N., Altman A., Tsongalis G.J. Clin. Chim. Acta 321:49-53(2002) [PubMed: 12031592] [Abstract] Cited for: VARIANT XLSA TYR-159.
[12]	"C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload." Whatley S.D., Ducamp S., Gouya L., Grandchamp B., Beaumont C., Badminton M.N., Elder G.H., Holme S.A., Anstey A.V., Parker M., Corrigall A.V., Meissner P.N., Hift R.J., Marsden J.T., Ma Y., Mieli-Vergani G., Deybach J.C., Puy H. Am. J. Hum. Genet. 83:408-414(2008) [PubMed: 18760763] [Abstract] Cited for: INVOLVEMENT IN XLDPT.
[13]	"New mutation in erythroid-specific delta-aminolevulinate synthase as the cause of X-linked sideroblastic anemia responsive to pyridoxine." Kucerova J., Horvathova M., Mojzikova R., Belohlavkova P., Cermak J., Divoky V. Acta Haematol. 125:193-197(2011) [PubMed: 21252495] [Abstract] Cited for: VARIANTS XLSA GLU-156; CYS-452 AND HIS-452, CHARACTERIZATION OF VARIANT XLSA GLU-156.
[14]	"ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria." To-Figueras J., Ducamp S., Clayton J., Badenas C., Delaby C., Ged C., Lyoumi S., Gouya L., de Verneuil H., Beaumont C., Ferreira G.C., Deybach J.C., Herrero C., Puy H. Blood 118:1443-1451(2011) [PubMed: 21653323] [Abstract] Cited for: VARIANT PHE-586, CHARACTERIZATION OF VARIANT PHE-586, POSSIBLE ROLE AS MODIFIER GENE IN ERYTHROPOIETIC DISORDERS.
[15]	"Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations." Ducamp S., Kannengiesser C., Touati M., Garcon L., Guerci-Bresler A., Guichard J.F., Vermylen C., Dochir J., Poirel H.A., Fouyssac F., Mansuy L., Leroux G., Tertian G., Girot R., Heimpel H., Matthes T., Talbi N., Deybach J.C. , Beaumont C., Puy H., Grandchamp B. Hum. Mutat. 32:590-597(2011) [PubMed: 21309041] [Abstract] Cited for: VARIANTS XLSA HIS-170; HIS-218; LYS-242; ASN-263; LEU-339; CYS-375; HIS-411; GLY-452 AND HIS-572, VARIANT LEU-520, CHARACTERIZATION OF VARIANTS XLSA HIS-170; HIS-218; LYS-242; ASN-263; LEU-339; CYS-375; HIS-411; GLY-452 AND HIS-572.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	X56352 mRNA. Translation: CAA39795.1. Different initiation. X60364 mRNA. Translation: CAA42916.1. AF068624 Genomic DNA. Translation: AAC39838.1. Z83821 Genomic DNA. No translation available. AL020991 Genomic DNA. Translation: CAA15886.1.
IPI	IPI00304949.
PIR	SYHUAE. S16347.
RefSeq	NP_000023.2. NM_000032.4.
UniGene	Hs.522666. Hs.555936.
3D structure databases
ProteinModelPortal	P22557.
SMR	P22557. Positions 1-49, 144-542.
ModBase	Search...
Protein-protein interaction databases
IntAct	P22557. 1 interaction.
STRING	P22557.
PTM databases
PhosphoSite	P22557.
Polymorphism databases
DMDM	20141346.
Proteomic databases
PRIDE	P22557.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000330807; ENSP00000332369; ENSG00000158578.
GeneID	212.
KEGG	hsa:212.
UCSC	uc004dua.2. human.
Organism-specific databases
CTD	212.
GeneCards	GC0XM055053.
H-InvDB	HIX0016826.
HGNC	HGNC:397. ALAS2.
HPA	HPA001638.
MIM	300751. phenotype. 300752. phenotype. 301300. gene.
neXtProt	NX_P22557.
Orphanet	79278. Erythropoietic protoporphyria. 75563. X-linked sideroblastic anemia.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG08438.
HOGENOM	HBG649839.
HOVERGEN	HBG005954.
InParanoid	P22557.
OMA	HLKESNE.
OrthoDB	EOG4H19VB.
PhylomeDB	P22557.
Enzyme and pathway databases
Reactome	REACT_111217. Metabolism.
Gene expression databases
ArrayExpress	P22557.
Bgee	P22557.
CleanEx	HS_ALAS2.
Genevestigator	P22557.
GermOnline	ENSG00000158578. Homo sapiens.
Family and domain databases
InterPro	IPR010961. 4pyrrol_synth_NH2levulA_synth. IPR015118. 5aminolev_synth_preseq. IPR001917. Aminotrans_II_pyridoxalP_BS. IPR004839. Aminotransferase_I/II. IPR015424. PyrdxlP-dep_Trfase_major_dom. IPR015421. PyrdxlP-dep_Trfase_major_sub1. IPR015422. PyrdxlP-dep_Trfase_major_sub2. [Graphical view]
Gene3D	G3DSA:3.40.640.10. PyrdxlP-dep_Trfase_major_sub1. 1 hit. G3DSA:3.90.1150.10. PyrdxlP-dep_Trfase_major_sub2. 1 hit.
KO	K00643.
Pfam	PF00155. Aminotran_1_2. 1 hit. PF09029. Preseq_ALAS. 1 hit. [Graphical view]
SUPFAM	SSF53383. PyrdxlP-dep_Trfase_major. 1 hit.
TIGRFAMs	TIGR01821. 5aminolev_synth. 1 hit.
PROSITE	PS00599. AA_TRANSFER_CLASS_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
DrugBank	DB00145. Glycine.
NextBio	852.
SOURCE	Search...

Entry information

Entry name

HEM0_HUMAN

Accession

Primary (citable) accession number: P22557
Secondary accession number(s): Q13735

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	January 23, 2002
Last modified:	January 25, 2012
This is version 134 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.