P40939 (ECHA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Trifunctional enzyme subunit alpha, mitochondrial

Alternative name(s):
78 kDa gastrin-binding protein
TP-alpha

Including the following 2 domains:

1. Long-chain enoyl-CoA hydratase
   EC=4.2.1.17
2. Long chain 3-hydroxyacyl-CoA dehydrogenase
   EC=1.1.1.211

Gene names

Name:	HADHA
Synonyms:	HADH

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	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. A long-chain (S)-3-hydroxyacyl-CoA + NAD+ = a long-chain 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	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 three enzyme activities of the TFP complex. Note: The disease is caused by mutations affecting the gene represented in this entry. 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Maternal acute fatty liver of pregnancy (AFLP) [MIM:609016]: 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). Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10
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
Technical term	Complete proteome Multifunctional enzyme Reference proteome
Gene Ontology (GO)
Biological_process	cardiolipin acyl-chain remodeling Traceable author statement. Source: Reactome fatty acid beta-oxidation Traceable author statement. Source: Reactome glycerophospholipid biosynthetic process Traceable author statement. Source: Reactome response to drug Inferred from electronic annotation. Source: Compara response to insulin stimulus Inferred from electronic annotation. Source: Compara
Cellular_component	mitochondrial fatty acid beta-oxidation multienzyme complex Inferred from electronic annotation. Source: Compara mitochondrial inner membrane Traceable author statement. Source: Reactome mitochondrial nucleoid Inferred from direct assay PubMed 18063578. Source: BHF-UCL nucleolus Inferred from direct assay. Source: HPA
Molecular_function	3-hydroxyacyl-CoA dehydrogenase activity Traceable author statement Ref.1. Source: ProtInc NAD binding Inferred from electronic annotation. Source: Compara acetyl-CoA C-acetyltransferase activity Traceable author statement Ref.1. Source: ProtInc enoyl-CoA hydratase activity Traceable author statement Ref.1. Source: ProtInc fatty-acyl-CoA binding Inferred from electronic annotation. Source: Compara long-chain-3-hydroxyacyl-CoA dehydrogenase activity Inferred from electronic annotation. Source: EC long-chain-enoyl-CoA hydratase activity Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GABARAP	O95166	5	EBI-356720,EBI-712001
GABARAPL1	Q9H0R8	4	EBI-356720,EBI-746969
GABARAPL2	P60520	4	EBI-356720,EBI-720116
MAP1LC3B	Q9GZQ8	4	EBI-356720,EBI-373144

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.7
	Modified residue	303	1	N6-acetyllysine Ref.7
	Modified residue	326	1	N6-acetyllysine By similarity
	Modified residue	350	1	N6-acetyllysine By similarity
	Modified residue	406	1	N6-acetyllysine Ref.7
	Modified residue	505	1	N6-acetyllysine Ref.7
	Modified residue	540	1	N6-acetyllysine Ref.7
	Modified residue	569	1	N6-acetyllysine By similarity
	Modified residue	644	1	N6-acetyllysine Ref.7
	Modified residue	728	1	N6-acetyllysine By similarity
Natural variations
	Natural variant	282	1	V → D in TFP deficiency; mild phenotype with slowly progressive myopathy and sensorimotor polyneuropathy. Ref.13		VAR_021125
	Natural variant	305	1	I → N in TFP deficiency; mild phenotype with slowly progressive myopathy and sensorimotor polyneuropathy. Ref.13		VAR_021126
	Natural variant	342	1	L → P in LCHAD deficiency. Ref.12		VAR_021127
	Natural variant	358	1	Q → K. Corresponds to variant rs10200182 [ dbSNP | Ensembl ].		VAR_048908
	Natural variant	510	1	E → Q in AFLP and LCHAD deficiency; loss of activity. Ref.9 Ref.10 Ref.11 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 [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: SUBUNIT.
[7]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-295; LYS-303; LYS-406; LYS-505; LYS-540 AND LYS-644, MASS SPECTROMETRY.
[8]	"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].
[9]	"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] [Europe PMC] [Abstract] Cited for: VARIANT LCHAD DEFICIENCY GLN-510.
[10]	"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] [Europe PMC] [Abstract] Cited for: VARIANT AFLP GLN-510.
[11]	"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] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANT LCHAD DEFICIENCY GLN-510.
[12]	"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] [Europe PMC] [Abstract] Cited for: VARIANTS LCHAD DEFICIENCY PRO-342 AND GLN-510.
[13]	"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] [Europe PMC] [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. NM_000182.4.
UniGene	Hs.516032.
3D structure databases
ProteinModelPortal	P40939.
ModBase	Search...
Protein-protein interaction databases
IntAct	P40939. 27 interactions.
MINT	MINT-1159893.
STRING	9606.ENSP00000370023.
PTM databases
PhosphoSite	P40939.
Polymorphism databases
DMDM	20141376.
2D gel databases
REPRODUCTION-2DPAGE	IPI00031522.
UCD-2DPAGE	P40939.
Proteomic databases
PaxDb	P40939.
PeptideAtlas	P40939.
PRIDE	P40939.
Protocols and materials databases
DNASU	3030.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000380649; ENSP00000370023; ENSG00000084754.
GeneID	3030.
KEGG	hsa:3030.
UCSC	uc002rgy.3. human.
Organism-specific databases
CTD	3030.
GeneCards	GC02M026413.
HGNC	HGNC:4801. HADHA.
HPA	HPA015536.
MIM	600890. gene. 609015. phenotype. 609016. phenotype.
neXtProt	NX_P40939.
Orphanet	243367. Acute fatty liver of pregnancy. 5. Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. 746. Mitochondrial trifunctional protein deficiency.
PharmGKB	PA29175.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG1250.
HOGENOM	HOG000261346.
HOVERGEN	HBG005557.
InParanoid	P40939.
KO	K07515.
OMA	SPKRDKG.
OrthoDB	EOG4FBHSD.
PhylomeDB	P40939.
Enzyme and pathway databases
Reactome	REACT_111217. Metabolism.
SABIO-RK	P40939.
UniPathway	UPA00659.
Gene expression databases
ArrayExpress	P40939.
Bgee	P40939.
CleanEx	HS_HADH. HS_HADHA.
Genevestigator	P40939.
GermOnline	ENSG00000084754. Homo sapiens.
Family and domain databases
Gene3D	1.10.1040.10. 2 hits. 3.40.50.720. 1 hit.
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_superfam. IPR013328. DH_multihelical. IPR018376. Enoyl-CoA_hyd/isom_CS. IPR012803. Fa_ox_alpha_mit. IPR016040. NAD(P)-bd_dom. [Graphical view]
Pfam	PF00725. 3HCDH. 2 hits. PF02737. 3HCDH_N. 1 hit. PF00378. ECH. 1 hit. [Graphical view]
SUPFAM	SSF48179. 6DGDH_C_like. 2 hits.
TIGRFAMs	TIGR02441. fa_ox_alpha_mit. 1 hit.
PROSITE	PS00067. 3HCDH. 1 hit. PS00166. ENOYL_COA_HYDRATASE. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	HADHA. human.
DrugBank	DB00157. NADH.
GenomeRNAi	3030.
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:	May 1, 2013
This is version 153 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.