Q9H2P9 (DPH5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Diphthine synthase
EC=2.1.1.98

Alternative name(s):
Diphthamide biosynthesis methyltransferase

Gene names

Name:	DPH5
ORF Names:	AD-018, CGI-30, HSPC143, NPD015

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	285 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	S-adenosyl-L-methionine-dependent methyltransferase that catalyzes the trimethylation of the amino group of the modified target histidine residue in translation elongation factor 2 (EF-2), to form an intermediate called diphthine. The three successive methylation reactions represent the second step of diphthamide biosynthesis By similarity.
Catalytic activity	3 S-adenosyl-L-methionine + 2-(3-carboxy-3-aminopropyl)-L-histidine = 3 S-adenosyl-L-homocysteine + 2-(3-carboxy-3-(trimethylammonio)propyl)-L-histidine.
Pathway	Protein modification; peptidyl-diphthamide biosynthesis.
Sequence similarities	Belongs to the diphthine synthase family.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing
Ligand	S-adenosyl-L-methionine
Molecular function	Methyltransferase Transferase
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	peptidyl-diphthamide biosynthetic process from peptidyl-histidine Non-traceable author statement PubMed 15485916. Source: UniProtKB
Molecular_function	diphthine synthase activity Non-traceable author statement PubMed 15485916. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 6 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9H2P9-1)

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 2 (identifier: Q9H2P9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     85-137: PFGATTHSDLVLRATKLGIPYRVIHNASIMNAVGCCGLQLYKFGETVSIVFWT → HL

Note: No experimental confirmation available.

Isoform 3 (identifier: Q9H2P9-3)

The sequence of this isoform differs from the canonical sequence as follows:
     88-143: ATTHSDLVLRATKLGIPYRVIHNASIMNAVGCCGLQLYKFGETVSIVFWTDTWRPE → HLETR

Note: No experimental confirmation available.

Isoform 4 (identifier: Q9H2P9-4)

The sequence of this isoform differs from the canonical sequence as follows:
     117-141: VGCCGLQLYKFGETVSIVFWTDTWR → EAAGGYRYISLERQVLLVFGQTLGG

Note: No experimental confirmation available.

Isoform 5 (identifier: Q9H2P9-5)

The sequence of this isoform differs from the canonical sequence as follows:
     134-137: VFWT → MLISVMLHSLWLVIHL

Note: No experimental confirmation available.

Isoform 6 (identifier: Q9H2P9-6)

The sequence of this isoform differs from the canonical sequence as follows:
     212-212: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 285	285	Diphthine synthase		PRO_0000156133
Regions
	Region	112 – 113	2	S-adenosyl-L-methionine binding By similarity
Sites
	Binding site	9	1	S-adenosyl-L-methionine; via carbonyl oxygen By similarity
	Binding site	84	1	S-adenosyl-L-methionine; via amide nitrogen and carbonyl oxygen By similarity
	Binding site	87	1	S-adenosyl-L-methionine; via carbonyl oxygen By similarity
	Binding site	163	1	S-adenosyl-L-methionine; via amide nitrogen and carbonyl oxygen By similarity
	Binding site	225	1	S-adenosyl-L-methionine; via amide nitrogen and carbonyl oxygen By similarity
	Binding site	250	1	S-adenosyl-L-methionine; via carbonyl oxygen By similarity
Natural variations
	Alternative sequence	85 – 137	53	PFGAT…IVFWT → HL in isoform 2.		VSP_008508
	Alternative sequence	88 – 143	56	ATTHS…TWRPE → HLETR in isoform 3.		VSP_008509
	Alternative sequence	117 – 141	25	VGCCG…TDTWR → EAAGGYRYISLERQVLLVFG QTLGG in isoform 4.		VSP_008510
	Alternative sequence	134 – 137	4	VFWT → MLISVMLHSLWLVIHL in isoform 5.		VSP_008511
	Alternative sequence	212	1	Missing in isoform 6.		VSP_043444
Experimental info
	Sequence conflict	107	1	V → G in AAG44563. Ref.4
	Sequence conflict	285	1	L → FEHRYFHCLM in AAF67485. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 10, 2003. Version 2. Checksum: 1348631C25BC624E	FASTA	285	31,651
	10 20 30 40 50 60 MLYLIGLGLG DAKDITVKGL EVVRRCSRVY LEAYTSVLTV GKEALEEFYG RKLVVADREE 70 80 90 100 110 120 VEQEADNILK DADISDVAFL VVGDPFGATT HSDLVLRATK LGIPYRVIHN ASIMNAVGCC 130 140 150 160 170 180 GLQLYKFGET VSIVFWTDTW RPESFFDKVK KNRQNGMHTL CLLDIKVKEQ SLENLIKGRK 190 200 210 220 230 240 IYEPPRYMSV NQAAQQLLEI VQNQRIRGEE PAVTEETLCV GLARVGADDQ KIAAGTLRQM 250 260 270 280 CTVDLGEPLH SLIITGGSIH PMEMEMLSLF SIPENSSESQ SINGL
	Isoform 2 [UniParc]. Checksum: CAA1ABE0A11AF714	FASTA	234	26,122
	10 20 30 40 50 60 MLYLIGLGLG DAKDITVKGL EVVRRCSRVY LEAYTSVLTV GKEALEEFYG RKLVVADREE 70 80 90 100 110 120 VEQEADNILK DADISDVAFL VVGDHLDTWR PESFFDKVKK NRQNGMHTLC LLDIKVKEQS 130 140 150 160 170 180 LENLIKGRKI YEPPRYMSVN QAAQQLLEIV QNQRIRGEEP AVTEETLCVG LARVGADDQK 190 200 210 220 230 IAAGTLRQMC TVDLGEPLHS LIITGGSIHP MEMEMLSLFS IPENSSESQS INGL
	Isoform 3 [UniParc]. Checksum: 86A9E6761145DFBA	FASTA	234	26,025
	10 20 30 40 50 60 MLYLIGLGLG DAKDITVKGL EVVRRCSRVY LEAYTSVLTV GKEALEEFYG RKLVVADREE 70 80 90 100 110 120 VEQEADNILK DADISDVAFL VVGDPFGHLE TRSFFDKVKK NRQNGMHTLC LLDIKVKEQS 130 140 150 160 170 180 LENLIKGRKI YEPPRYMSVN QAAQQLLEIV QNQRIRGEEP AVTEETLCVG LARVGADDQK 190 200 210 220 230 IAAGTLRQMC TVDLGEPLHS LIITGGSIHP MEMEMLSLFS IPENSSESQS INGL
	Isoform 4 [UniParc]. Checksum: 2784D835EB96EFC2	FASTA	285	31,440
	10 20 30 40 50 60 MLYLIGLGLG DAKDITVKGL EVVRRCSRVY LEAYTSVLTV GKEALEEFYG RKLVVADREE 70 80 90 100 110 120 VEQEADNILK DADISDVAFL VVGDPFGATT HSDLVLRATK LGIPYRVIHN ASIMNAEAAG 130 140 150 160 170 180 GYRYISLERQ VLLVFGQTLG GPESFFDKVK KNRQNGMHTL CLLDIKVKEQ SLENLIKGRK 190 200 210 220 230 240 IYEPPRYMSV NQAAQQLLEI VQNQRIRGEE PAVTEETLCV GLARVGADDQ KIAAGTLRQM 250 260 270 280 CTVDLGEPLH SLIITGGSIH PMEMEMLSLF SIPENSSESQ SINGL
	Isoform 5 [UniParc]. Checksum: E0D27EEEF0B9849D	FASTA	297	33,005
	10 20 30 40 50 60 MLYLIGLGLG DAKDITVKGL EVVRRCSRVY LEAYTSVLTV GKEALEEFYG RKLVVADREE 70 80 90 100 110 120 VEQEADNILK DADISDVAFL VVGDPFGATT HSDLVLRATK LGIPYRVIHN ASIMNAVGCC 130 140 150 160 170 180 GLQLYKFGET VSIMLISVML HSLWLVIHLD TWRPESFFDK VKKNRQNGMH TLCLLDIKVK 190 200 210 220 230 240 EQSLENLIKG RKIYEPPRYM SVNQAAQQLL EIVQNQRIRG EEPAVTEETL CVGLARVGAD 250 260 270 280 290 DQKIAAGTLR QMCTVDLGEP LHSLIITGGS IHPMEMEMLS LFSIPENSSE SQSINGL
	Isoform 6 [UniParc]. Checksum: 862A9762E32AA574	FASTA	284	31,580
	10 20 30 40 50 60 MLYLIGLGLG DAKDITVKGL EVVRRCSRVY LEAYTSVLTV GKEALEEFYG RKLVVADREE 70 80 90 100 110 120 VEQEADNILK DADISDVAFL VVGDPFGATT HSDLVLRATK LGIPYRVIHN ASIMNAVGCC 130 140 150 160 170 180 GLQLYKFGET VSIVFWTDTW RPESFFDKVK KNRQNGMHTL CLLDIKVKEQ SLENLIKGRK 190 200 210 220 230 240 IYEPPRYMSV NQAAQQLLEI VQNQRIRGEE PVTEETLCVG LARVGADDQK IAAGTLRQMC 250 260 270 280 TVDLGEPLHS LIITGGSIHP MEMEMLSLFS IPENSSESQS INGL

References

[1]	"Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics." Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C. Genome Res. 10:703-713(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
[2]	"Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning." Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M. , Zhou J., Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L. Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Adrenal gland.
[3]	"Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells." Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G., Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W., Tao J., Huang Q.-H., Zhou J., Hu G.-X. , Gu J., Chen S.-J., Chen Z. Genome Res. 10:1546-1560(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). Tissue: Umbilical cord blood.
[4]	Yang Y., Xu X., Gao G., Xiao H., Chen Z., Han Z. Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). Tissue: Pituitary.
[5]	"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] (ISOFORM 6).
[6]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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 1). Tissue: Eye.
[9]	"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].
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF132964 mRNA. Translation: AAD27739.1. AF157319 mRNA. Translation: AAF67485.1. AF161492 mRNA. Translation: AAF29107.1. AF248965 mRNA. Translation: AAG44563.1. AK289351 mRNA. Translation: BAF82040.1. AC093157 Genomic DNA. No translation available. CH471097 Genomic DNA. Translation: EAW72933.1. CH471097 Genomic DNA. Translation: EAW72937.1. CH471097 Genomic DNA. Translation: EAW72938.1. CH471097 Genomic DNA. Translation: EAW72940.1. BC053857 mRNA. Translation: AAH53857.1.
IPI	IPI00006419. IPI00375822. IPI00375823. IPI00375824. IPI00902709. IPI00941449.
RefSeq	NP_001070862.1. NM_001077394.1. NP_001070863.1. NM_001077395.1. NP_057042.2. NM_015958.2.
UniGene	Hs.440776.
3D structure databases
ProteinModelPortal	Q9H2P9.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000359127.
PTM databases
PhosphoSite	Q9H2P9.
Polymorphism databases
DMDM	46397414.
Proteomic databases
PaxDb	Q9H2P9.
PRIDE	Q9H2P9.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000342173; ENSP00000339630; ENSG00000117543. ENST00000370109; ENSP00000359127; ENSG00000117543. ENST00000488176; ENSP00000418282; ENSG00000117543.
GeneID	51611.
KEGG	hsa:51611.
UCSC	uc001dts.2. human. uc001dty.2. human.
Organism-specific databases
CTD	51611.
GeneCards	GC01M101455.
H-InvDB	HIX0023161.
HGNC	HGNC:24270. DPH5.
HPA	HPA046439.
MIM	611075. gene.
neXtProt	NX_Q9H2P9.
PharmGKB	PA142671956.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG1798.
HOGENOM	HOG000205302.
HOVERGEN	HBG044879.
InParanoid	Q9H2P9.
KO	K00586.
OMA	TTHVDLR.
OrthoDB	EOG4M65J4.
PhylomeDB	Q9H2P9.
Enzyme and pathway databases
UniPathway	UPA00559.
Gene expression databases
ArrayExpress	Q9H2P9.
Bgee	Q9H2P9.
CleanEx	HS_DPH5.
Genevestigator	Q9H2P9.
GermOnline	ENSG00000117543. Homo sapiens.
Family and domain databases
Gene3D	3.30.950.10. 1 hit. 3.40.1010.10. 1 hit.
InterPro	IPR000878. 4pyrrol_Mease. IPR014777. 4pyrrole_Mease_sub1. IPR014776. 4pyrrole_Mease_sub2. IPR004551. Dphthn_synthase. [Graphical view]
Pfam	PF00590. TP_methylase. 1 hit. [Graphical view]
PIRSF	PIRSF036432. Diphthine_synth. 1 hit.
SUPFAM	SSF53790. Cor/por_Metransf. 1 hit.
TIGRFAMs	TIGR00522. dph5. 1 hit.
ProtoNet	Search...
Other
ChiTaRS	DPH5. human.
GenomeRNAi	51611.
NextBio	55510.
SOURCE	Search...

Entry information

Entry name

DPH5_HUMAN

Accession

Primary (citable) accession number: Q9H2P9
Secondary accession number(s): A8JZY6 , D3DT62, Q9P017, Q9P0I4, Q9Y319

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 10, 2003
Last sequence update:	October 10, 2003
Last modified:	May 1, 2013
This is version 94 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.