Q15165 (PON2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serum paraoxonase/arylesterase 2
Short name=PON 2
EC=3.1.1.2
EC=3.1.1.81

Alternative name(s):
Aromatic esterase 2
Short name=A-esterase 2
Serum aryldialkylphosphatase 2

Gene names

Name:

PON2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	354 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Capable of hydrolyzing lactones and a number of aromatic carboxylic acid esters. Has antioxidant activity. Is not associated with high density lipoprotein. Prevents LDL lipid peroxidation, reverses the oxidation of mildly oxidized LDL, and inhibits the ability of MM-LDL to induce monocyte chemotaxis. Ref.9 Ref.10
Catalytic activity	A phenyl acetate + H2O = a phenol + acetate. Ref.10 An N-acyl-L-homoserine lactone + H2O = an N-acyl-L-homoserine. Ref.10
Cofactor	Binds 2 calcium ions per subunit By similarity.
Subunit structure	Homotrimer. Ref.10
Subcellular location	Membrane; Peripheral membrane protein Ref.9.
Tissue specificity	Widely expressed with highest expression in liver, lung, placenta, testis and heart. Ref.9
Post-translational modification	The signal sequence is not cleaved By similarity.
Sequence similarities	Belongs to the paraoxonase family.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal
Ligand	Calcium Metal-binding
Molecular function	Hydrolase
PTM	Disulfide bond Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	aromatic compound catabolic process Inferred from direct assay Ref.10. Source: BHF-UCL response to oxidative stress Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular region Inferred from electronic annotation. Source: InterPro lysosome Inferred from electronic annotation. Source: Compara mitochondrion Inferred from electronic annotation. Source: Compara nucleus Inferred from electronic annotation. Source: Compara plasma membrane Inferred from direct assay Ref.10. Source: BHF-UCL
Molecular_function	arylesterase activity Traceable author statement Ref.1. Source: ProtInc identical protein binding Inferred from direct assay Ref.10. Source: BHF-UCL metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 2 (identifier: Q15165-2)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 1 (identifier: Q15165-1)

The sequence of this isoform differs from the canonical sequence as follows:
     1-16: MGRLVAVGLLGIALAL → MGAWVGCGLAGDRAGF

Isoform 3 (identifier: Q15165-3)

The sequence of this isoform differs from the canonical sequence as follows:
     123-134: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 354	354	Serum paraoxonase/arylesterase 2		PRO_0000223287
	Signal peptide	1 – ?		Not cleaved By similarity
Sites
	Active site	114	1	Proton acceptor By similarity
	Metal binding	53	1	Calcium 1; catalytic By similarity
	Metal binding	54	1	Calcium 2 By similarity
	Metal binding	116	1	Calcium 2; via carbonyl oxygen By similarity
	Metal binding	167	1	Calcium 1; catalytic By similarity
	Metal binding	168	1	Calcium 2 By similarity
	Metal binding	223	1	Calcium 1; catalytic By similarity
	Metal binding	268	1	Calcium 1; catalytic By similarity
	Metal binding	269	1	Calcium 1; catalytic By similarity
Amino acid modifications
	Glycosylation	254	1	N-linked (GlcNAc...) Ref.11
	Glycosylation	269	1	N-linked (GlcNAc...) Potential
	Glycosylation	323	1	N-linked (GlcNAc...) Potential
	Disulfide bond	42 ↔ 352		By similarity
Natural variations
	Alternative sequence	1 – 16	16	MGRLV…IALAL → MGAWVGCGLAGDRAGF in isoform 1.		VSP_004533
	Alternative sequence	123 – 134	12	Missing in isoform 3.		VSP_040715
	Natural variant	148	1	A → G Associated with elevated mean fasting plasma glucose level. Ref.2 Ref.5 Ref.13 Corresponds to variant rs12026 [ dbSNP | Ensembl ].		VAR_006045
	Natural variant	172	1	V → L. Ref.5 Corresponds to variant rs17876152 [ dbSNP | Ensembl ].		VAR_020786
	Natural variant	311	1	C → S Associated with increased risk of coronary heart disease; CHD. Ref.1 Ref.2 Ref.3 Ref.4 Ref.5 Ref.7 Ref.14 Corresponds to variant rs7493 [ dbSNP | Ensembl ].		VAR_006046
Experimental info
	Sequence conflict	49 – 50	2	EA → VW in AAC27945. Ref.2
	Sequence conflict	53	1	E → D in BAG37646. Ref.4
	Sequence conflict	63	1	A → V in BAG58797. Ref.4
	Sequence conflict	194	1	E → G in AAC41995. Ref.1
	Sequence conflict	282	1	G → V in AAC27944. Ref.2
	Sequence conflict	282	1	G → V in BAD89420. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 2 [UniParc]. Last modified March 8, 2011. Version 3. Checksum: 05CEDC84D5E7EC2A	FASTA	354	39,397
	10 20 30 40 50 60 MGRLVAVGLL GIALALLGER LLALRNRLKA SREVESVDLP HCHLIKGIEA GSEDIDILPN 70 80 90 100 110 120 GLAFFSVGLK FPGLHSFAPD KPGGILMMDL KEEKPRAREL RISRGFDLAS FNPHGISTFI 130 140 150 160 170 180 DNDDTVYLFV VNHPEFKNTV EIFKFEEAEN SLLHLKTVKH ELLPSVNDIT AVGPAHFYAT 190 200 210 220 230 240 NDHYFSDPFL KYLETYLNLH WANVVYYSPN EVKVVAEGFD SANGINISPD DKYIYVADIL 250 260 270 280 290 300 AHEIHVLEKH TNMNLTQLKV LELDTLVDNL SIDPSSGDIW VGCHPNGQKL FVYDPNNPPS 310 320 330 340 350 SEVLRIQNIL CEKPTVTTVY ANNGSVLQGS SVASVYDGKL LIGTLYHRAL YCEL
	Isoform 1 [UniParc]. Checksum: AAA1980D3850889D	FASTA	354	39,398
	10 20 30 40 50 60 MGAWVGCGLA GDRAGFLGER LLALRNRLKA SREVESVDLP HCHLIKGIEA GSEDIDILPN 70 80 90 100 110 120 GLAFFSVGLK FPGLHSFAPD KPGGILMMDL KEEKPRAREL RISRGFDLAS FNPHGISTFI 130 140 150 160 170 180 DNDDTVYLFV VNHPEFKNTV EIFKFEEAEN SLLHLKTVKH ELLPSVNDIT AVGPAHFYAT 190 200 210 220 230 240 NDHYFSDPFL KYLETYLNLH WANVVYYSPN EVKVVAEGFD SANGINISPD DKYIYVADIL 250 260 270 280 290 300 AHEIHVLEKH TNMNLTQLKV LELDTLVDNL SIDPSSGDIW VGCHPNGQKL FVYDPNNPPS 310 320 330 340 350 SEVLRIQNIL CEKPTVTTVY ANNGSVLQGS SVASVYDGKL LIGTLYHRAL YCEL
	Isoform 3 [UniParc]. Checksum: 71F47B3E08154500	FASTA	342	37,996
	10 20 30 40 50 60 MGRLVAVGLL GIALALLGER LLALRNRLKA SREVESVDLP HCHLIKGIEA GSEDIDILPN 70 80 90 100 110 120 GLAFFSVGLK FPGLHSFAPD KPGGILMMDL KEEKPRAREL RISRGFDLAS FNPHGISTFI 130 140 150 160 170 180 DNEFKNTVEI FKFEEAENSL LHLKTVKHEL LPSVNDITAV GPAHFYATND HYFSDPFLKY 190 200 210 220 230 240 LETYLNLHWA NVVYYSPNEV KVVAEGFDSA NGINISPDDK YIYVADILAH EIHVLEKHTN 250 260 270 280 290 300 MNLTQLKVLE LDTLVDNLSI DPSSGDIWVG CHPNGQKLFV YDPNNPPSSE VLRIQNILCE 310 320 330 340 KPTVTTVYAN NGSVLQGSSV ASVYDGKLLI GTLYHRALYC EL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family." Primo-Parmo S.L., Sorenson R.C., Teiber J., La Du B.N. Genomics 33:498-507(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-311. Tissue: Liver.
[2]	"Human PON2 gene at 7q21.3: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence." Mochizuki H., Scherer S.W., Xi T., Nickle D.C., Majer M., Huizenga J.J., Tsui L.-C., Prochazka M. Gene 213:149-157(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 50-67, ALTERNATIVE SPLICING, VARIANTS GLY-148 AND SER-311.
[3]	"Paraoxonase mRNA,nirs splice variant1." Sameshima E., Tabata Y., Hayashi A., Iida K., Mitsuyama M., Kanai S., Furuya T., Saito T. Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), VARIANT SER-311.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), VARIANT SER-311. Tissue: Subthalamic nucleus and Testis.
[5]	SeattleSNPs variation discovery resource Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-148; LEU-172 AND SER-311.
[6]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"Human chromosome 7: DNA sequence and biology." Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., Kanematsu E., Gentles S. , Christopoulos C.C., Choufani S., Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., Adams M.D., Tsui L.-C. Science 300:767-772(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT SER-311.
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Skin.
[9]	"Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein." Ng C.J., Wadleigh D.J., Gangopadhyay A., Hama S., Grijalva V.R., Navab M., Fogelman A.M., Reddy S.T. J. Biol. Chem. 276:44444-44449(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[10]	"Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities." Draganov D.I., Teiber J.F., Speelman A., Osawa Y., Sunahara R., La Du B.N. J. Lipid Res. 46:1239-1247(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBUNIT.
[11]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-254, MASS SPECTROMETRY. Tissue: Liver.
[12]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus." Hegele R.A., Connelly P.W., Scherer S.W., Hanley A.J.G., Harris S.B., Tsui L.-C., Zinman B. J. Clin. Endocrinol. Metab. 82:3373-3377(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GLY-148.
[14]	"DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease." Sanghera D.K., Aston C.E., Saha N., Kamboh M.I. Am. J. Hum. Genet. 62:36-44(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SER-311.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

SHMPD

The Singapore human mutation and polymorphism database

Cross-references

Sequence databases
EMBL GenBank DDBJ	L48513 mRNA. Translation: AAC41995.1. AF001601 mRNA. Translation: AAC27944.1. AF001602 mRNA. Translation: AAC27945.1. AF001603 Genomic DNA. Translation: AAC27946.1. AB102891 mRNA. Translation: BAD89420.1. AK291103 mRNA. Translation: BAF83792.1. AK296029 mRNA. Translation: BAG58797.1. AK315209 mRNA. Translation: BAG37646.1. AY210982 Genomic DNA. Translation: AAO18083.1. AC005021 Genomic DNA. Translation: AAC62431.1. CH236949 Genomic DNA. Translation: EAL24131.1. BC040010 mRNA. Translation: AAH40010.1.
IPI	IPI00014958. IPI00290945. IPI00742670.
RefSeq	NP_000296.2. NM_000305.2.
UniGene	Hs.731646.
3D structure databases
ProteinModelPortal	Q15165.
SMR	Q15165. Positions 23-354.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q15165. 2 interactions.
STRING	9606.ENSP00000222572.
PTM databases
PhosphoSite	Q15165.
Polymorphism databases
DMDM	6174935.
Proteomic databases
PaxDb	Q15165.
PRIDE	Q15165.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000222572; ENSP00000222572; ENSG00000105854. ENST00000446142; ENSP00000405211; ENSG00000105854.
GeneID	5445.
KEGG	hsa:5445.
UCSC	uc003unu.3. human.
Organism-specific databases
CTD	5445.
GeneCards	GC07M095034.
HGNC	HGNC:9205. PON2.
HPA	CAB025430. HPA029193.
MIM	602447. gene.
neXtProt	NX_Q15165.
Orphanet	803. Amyotrophic lateral sclerosis.
PharmGKB	PA33530.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG68009.
HOVERGEN	HBG003604.
KO	K01045.
Gene expression databases
ArrayExpress	Q15165.
Bgee	Q15165.
CleanEx	HS_PON2.
Genevestigator	Q15165.
GermOnline	ENSG00000105854. Homo sapiens.
Family and domain databases
Gene3D	2.120.10.30. 1 hit.
InterPro	IPR011042. 6-blade_b-propeller_TolB-like. IPR002640. Arylesterase. IPR008364. Paraoxonase2. [Graphical view]
Pfam	PF01731. Arylesterase. 1 hit. [Graphical view]
PRINTS	PR01785. PARAOXONASE. PR01787. PARAOXONASE2.
ProtoNet	Search...
Other
GenomeRNAi	5445.
NextBio	21073.
SOURCE	Search...

Entry information

Entry name

PON2_HUMAN

Accession

Primary (citable) accession number: Q15165
Secondary accession number(s): A4D1H7 , B2RCP9, B4DJD5, O15114, O15115, O75856, Q5FBX7, Q86YL0

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	March 8, 2011
Last modified:	April 3, 2013
This is version 118 of the entry and version 3 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.