Reviewed, UniProtKB/Swiss-Prot P40939 (ECHA_HUMAN)

Names and origin

Protein names

Recommended name:
    Trifunctional enzyme subunit alpha, mitochondrial
Alternative name(s):
    TP-alpha
    78 kDa gastrin-binding protein
Including the following 2 domains:
    1- Recommended name:
            Long-chain enoyl-CoA hydratase
              EC=4.2.1.17
    2- Recommended name:
            Long chain 3-hydroxyacyl-CoA dehydrogenase
              EC=1.1.1.211

Gene names

Name:	HADHA
Synonyms:	HADH

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	763 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)

Function	Bifunctional subunit.
Catalytic activity	(3S)-3-hydroxyacyl-CoA = trans-2(or 3)-enoyl-CoA + H2O. (S)-3-hydroxyacyl-CoA + NAD+ = 3-oxoacyl-CoA + NADH.
Pathway	Lipid metabolism; fatty acid beta-oxidation.
Subunit structure	Octamer of 4 alpha (HADHA) and 4 beta (HADHB) subunits. Ref.6
Subcellular location	Mitochondrion.
Involvement in disease	Defects in HADHA are a cause of trifunctional protein deficiency (TFP deficiency) [MIM:609015]. The clinical manifestations are very variable and include hypoglycemia, cardiomyopathy and sudden death. Phenotypes with mainly hepatic and neuromyopathic involvement can also be distinguished. Biochemically, TFP deficiency is defined by the loss of all enzyme activities of the TFP complex. Defects in HADHA are the cause of long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency) [MIM:609016]. The clinical features are very similar to TFP deficiency. Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the other enzyme activities of the TFP complex are normal or only slightly reduced. Defects in HADHA are a cause of maternal acute fatty liver of pregnancy (AFLP) [MIM:609016]. AFLP is a severe maternal illness occurring during pregnancies with affected fetuses. This disease is associated with LCHAD deficiency and characterized by sudden unexplained infant death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). Ref.11
Sequence similarities	In the N-terminal section; belongs to the enoyl-CoA hydratase/isomerase family. In the central section; belongs to the 3-hydroxyacyl-CoA dehydrogenase family.

Ontologies

Keywords
Biological process	Fatty acid metabolism Lipid metabolism
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Transit peptide
Ligand	NAD
Molecular function	Lyase Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Multifunctional enzyme
Gene Ontology (GO)
Biological process	oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	fatty acid beta-oxidation multienzyme complex Inferred from electronic annotation. Source: InterPro mitochondrial nucleoid Inferred from direct assay. Source: UniProtKB
Molecular function	3-hydroxyacyl-CoA dehydrogenase activity Ref.1 Traceable author statement. Source: ProtInc acetyl-CoA C-acetyltransferase activity Ref.1 Traceable author statement. Source: ProtInc enoyl-CoA hydratase activity Ref.1 Traceable author statement. Source: ProtInc long-chain-3-hydroxyacyl-CoA dehydrogenase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Transit peptide	1 – 36	36	Mitochondrion Potential
	Chain	37 – 763	727	Trifunctional enzyme subunit alpha, mitochondrial		PRO_0000007403
Sites
	Site	151	1	Important for catalytic activity By similarity
	Site	173	1	Important for catalytic activity By similarity
Amino acid modifications
	Modified residue	129	1	N6-acetyllysine By similarity
	Modified residue	295	1	N6-acetyllysine Ref.9
	Modified residue	303	1	N6-acetyllysine Ref.9
	Modified residue	326	1	N6-acetyllysine By similarity
	Modified residue	350	1	N6-acetyllysine By similarity
	Modified residue	353	1	N6-acetyllysine Ref.9
	Modified residue	359	1	N6-acetyllysine Ref.9
	Modified residue	406	1	N6-acetyllysine Ref.9
	Modified residue	505	1	N6-acetyllysine Ref.9
	Modified residue	540	1	N6-acetyllysine Ref.9
	Modified residue	569	1	N6-acetyllysine By similarity
	Modified residue	644	1	N6-acetyllysine Ref.9
	Modified residue	728	1	N6-acetyllysine By similarity
	Modified residue	756	1	Phosphoserine Ref.7
Natural variations
	Natural variant	282	1	V → D in TFP deficiency; mild phenotype with slowly progressive myopathy and sensorimotor polyneuropathy. Ref.14		VAR_021125
	Natural variant	305	1	I → N in TFP deficiency; mild phenotype with slowly progressive myopathy and sensorimotor polyneuropathy. Ref.14		VAR_021126
	Natural variant	342	1	L → P in LCHAD deficiency. Ref.13		VAR_021127
	Natural variant	358	1	Q → K: dbSNP rs10200182.		VAR_048908
	Natural variant	510	1	E → Q in AFLP and LCHAD deficiency; loss of activity. Ref.11 Ref.13 Ref.10 Ref.12		VAR_002273
Experimental info
	Sequence conflict	146	1	L → V in BAA03941. Ref.1
	Sequence conflict	152	1	V → L in AAA56664. Ref.2
	Sequence conflict	171	1	T → A in AAA56664. Ref.2
	Sequence conflict	178	1	A → I in AAA56664. Ref.2
	Sequence conflict	197 – 198	2	AL → VF in AAA56664. Ref.2
	Sequence conflict	206	1	S → N in AAA56664. Ref.2
	Sequence conflict	211	1	R → S in AAA56664. Ref.2
	Sequence conflict	576	1	T → P in AAA56664. Ref.2
	Sequence conflict	694	1	L → S in BAA03941. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P40939-1 [UniParc]. Last modified April 3, 2002. Version 2. Checksum: 247FF7B4E48FB484	FASTA	763	83,000
	10 20 30 40 50 60 MVACRAIGIL SRFSAFRILR SRGYICRNFT GSSALLTRTH INYGVKGDVA VVRINSPNSK 70 80 90 100 110 120 VNTLSKELHS EFSEVMNEIW ASDQIRSAVL ISSKPGCFIA GADINMLAAC KTLQEVTQLS 130 140 150 160 170 180 QEAQRIVEKL EKSTKPIVAA INGSCLGGGL EVAISCQYRI ATKDRKTVLG TPEVLLGALP 190 200 210 220 230 240 GAGGTQRLPK MVGVPAALDM MLTGRSIRAD RAKKMGLVDQ LVEPLGPGLK PPEERTIEYL 250 260 270 280 290 300 EEVAITFAKG LADKKISPKR DKGLVEKLTA YAMTIPFVRQ QVYKKVEEKV RKQTKGLYPA 310 320 330 340 350 360 PLKIIDVVKT GIEQGSDAGY LCESQKFGEL VMTKESKALM GLYHGQVLCK KNKFGAPQKD 370 380 390 400 410 420 VKHLAILGAG LMGAGIAQVS VDKGLKTILK DATLTALDRG QQQVFKGLND KVKKKALTSF 430 440 450 460 470 480 ERDSIFSNLT GQLDYQGFEK ADMVIEAVFE DLSLKHRVLK EVEAVIPDHC IFASNTSALP 490 500 510 520 530 540 ISEIAAVSKR PEKVIGMHYF SPVDKMQLLE IITTEKTSKD TSASAVAVGL KQGKVIIVVK 550 560 570 580 590 600 DGPGFYTTRC LAPMMSEVIR ILQEGVDPKK LDSLTTSFGF PVGAATLVDE VGVDVAKHVA 610 620 630 640 650 660 EDLGKVFGER FGGGNPELLT QMVSKGFLGR KSGKGFYIYQ EGVKRKDLNS DMDSILASLK 670 680 690 700 710 720 LPPKSEVSSD EDIQFRLVTR FVNEAVMCLQ EGILATPAEG DIGAVFGLGF PPCLGGPFRF 730 740 750 760 VDLYGAQKIV DRLKKYEAAY GKQFTPCQLL ADHANSPNKK FYQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Structural analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation trifunctional protein." Kamijo T., Aoyama T., Komiyama A., Hashimoto T. Biochem. Biophys. Res. Commun. 199:818-825(1994) [PubMed: 8135828] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene." Zhang Q.X., Baldwin G.S. Biochim. Biophys. Acta 1219:567-575(1994) [PubMed: 7918661] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Amygdala.
[4]	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].
[5]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lymph.
[6]	"Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of the mutant enzyme in two patients." Kamijo T., Wanders R.J., Saudubray J.-M., Aoyama T., Komiyama A., Hashimoto T. J. Clin. Invest. 93:1740-1747(1994) [PubMed: 8163672] [Abstract] Cited for: SUBUNIT.
[7]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-756, MASS SPECTROMETRY. Tissue: Epithelium.
[8]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[9]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-129; LYS-295; LYS-303; LYS-326; LYS-353; LYS-359; LYS-406; LYS-505; LYS-540 AND LYS-644, MASS SPECTROMETRY.
[10]	"Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein." Ijlst L., Wanders R.J.A., Ushikubo S., Kamijo T., Hashimoto T. Biochim. Biophys. Acta 1215:347-350(1994) [PubMed: 7811722] [Abstract] Cited for: VARIANT LCHAD DEFICIENCY GLN-510.
[11]	"The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy." Sims H.F., Brackett J.C., Powell C.K., Treem W.R., Hale D.E., Bennett M.J., Gibson B., Shapiro S., Strauss A.W. Proc. Natl. Acad. Sci. U.S.A. 92:841-845(1995) [PubMed: 7846063] [Abstract] Cited for: VARIANT AFLP GLN-510.
[12]	"Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene." Ijlst L., Ruiter J.P.N., Hoovers J.M.N., Jakobs M.E., Wanders R.J.A. J. Clin. Invest. 98:1028-1033(1996) [PubMed: 8770876] [Abstract] Cited for: CHARACTERIZATION OF VARIANT LCHAD DEFICIENCY GLN-510.
[13]	"Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations." Ijlst L., Oostheim W., Ruiter J.P.N., Wanders R.J.A. J. Inherit. Metab. Dis. 20:420-422(1997) [PubMed: 9266371] [Abstract] Cited for: VARIANTS LCHAD DEFICIENCY PRO-342 AND GLN-510.
[14]	"Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation." Ibdah J.A., Tein I., Dionisi-Vici C., Bennett M.J., Ijlst L., Gibson B., Wanders R.J.A., Strauss A.W. J. Clin. Invest. 102:1193-1199(1998) [PubMed: 9739053] [Abstract] Cited for: VARIANTS TFP DEFICIENCY ASP-282 AND ASN-305.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	D16480 mRNA. Translation: BAA03941.1. U04627 mRNA. Translation: AAA56664.1. AK313027 mRNA. Translation: BAG35861.1. CH471053 Genomic DNA. Translation: EAX00703.1. BC009235 mRNA. Translation: AAH09235.1.
IPI	IPI00031522.
PIR	JC2108.
RefSeq	NP_000173.2.
UniGene	Hs.516032
3D structure databases
SMR	P40939. Positions 45-763.
ModBase	Search...
Protein-protein interaction databases
IntAct	P40939. 11 interactions.
STRING	P40939.
PTM databases
PhosphoSite	P40939.
2-D gel databases
REPRODUCTION-2DPAGE	IPI00031522.
Proteomic databases
PeptideAtlas	P40939.
PRIDE	P40939.
Genome annotation databases
Ensembl	ENST00000380649; ENSP00000370023; ENSG00000084754; Homo sapiens. [Genome view]
GeneID	3030.
KEGG	hsa:3030.
NMPDR	fig|9606.3.peg.17616.
UCSC	uc002rgy.1. human.
Organism-specific databases
CTD	3030.
GeneCards	GC02M026325.
H-InvDB	HIX0001890. HIX0077699.
HGNC	HGNC:4801. HADHA.
HPA	HPA015536.
MIM	600890. gene. 609015. phenotype. 609016. phenotype.
Orphanet	5. 3-hydroxyacyl-CoA dehydrogenase, long chain, deficiency of. 746. Mitochondrial trifunctional protein deficiency.
PharmGKB	PA29175.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG09923.
HOGENOM	HBG691737.
HOVERGEN	P40939.
InParanoid	P40939.
OMA	HATTSDE.
OrthoDB	EOG90CM27.
PhylomeDB	P40939.
Enzyme and pathway databases
BRENDA	1.1.1.211. 247. 4.2.1.17. 247.
Reactome	REACT_602. Metabolism of lipids and lipoproteins.
Gene expression databases
ArrayExpress	P40939.
Bgee	P40939.
CleanEx	HS_HADH. HS_HADHA.
Genevestigator	P40939.
GermOnline	ENSG00000084754. Homo sapiens.
Family and domain databases
InterPro	IPR006180. 3-OHacyl-CoA_DH_CS. IPR006176. 3-OHacyl-CoA_DH_NAD-bd. IPR006108. 3HC_DH_C. IPR008927. 6-PGluconate_DH_C-like. IPR001753. Crotonase_core. IPR013328. DH_multihelical. IPR018376. Enoyl-CoA_hyd/isom_CS. IPR012803. Fa_ox_alpha_mit. IPR016040. NAD(P)-bd_dom. [Graphical view]
Gene3D	G3DSA:1.10.1040.10. Opine_DH. 1 hit.
Pfam	PF00725. 3HCDH. 2 hits. PF02737. 3HCDH_N. 1 hit. PF00378. ECH. 1 hit. [Graphical view]
TIGRFAMs	TIGR02441. fa_ox_alpha_mit. 1 hit.
PROSITE	PS00067. 3HCDH. 1 hit. PS00166. ENOYL_COA_HYDRATASE. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB00157. NADH.
NextBio	11996.
SOURCE	Search...

Entry information

Entry name

ECHA_HUMAN

Accession

Primary (citable) accession number: P40939
Secondary accession number(s): B2R7L4, Q16679, Q96GT7

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	April 3, 2002
Last modified:	February 9, 2010
This is version 119 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.