Search Results

Overview

Uniprot IDP40939
Protein NameTrifunctional enzyme subunit alpha, mitochondrial
Gene NameHADHA
OrganismHomo sapiens

Kla Sites from experimental identification

Position Flanking peptide
166 RIATKDRKTVLGTPE
214 IRADRAKKMGLVDQL
262 KISPKRDKGLVEKLT
295 EKVRKQTKGLYPAPL
303 GLYPAPLKIIDVVKT
326 GYLCESQKFGELVMT
337 LVMTKESKALMGLYH
350 YHGQVLCKKNKFGAP
353 QVLCKKNKFGAPQKD
359 NKFGAPQKDVKHLAI
386 VSVDKGLKTILKDAT
390 KGLKTILKDATLTAL
406 RGQQQVFKGLNDKVK
411 VFKGLNDKVKKKALT
415 LNDKVKKKALTSFER
46 THINYGVKGDVAVVR
489 SEIAAVSKRPEKVIG
493 AVSKRPEKVIGMHYF
505 HYFSPVDKMQLLEII
516 LEIITTEKTSKDTSA
519 ITTEKTSKDTSASAV
531 SAVAVGLKQGKVIIV
540 GKVIIVVKDGPGFYT
569 LQEGVDPKKLDSLTT
60 RINSPNSKVNTLSKE
605 HVAEDLGKVFGERFG
625 LLTQMVSKGFLGRKS
634 FLGRKSGKGFYIYQE
644 YIYQEGVKRKDLNSD
664 ASLKLPPKSEVSSDE
728 VDLYGAQKIVDRLKK
735 KIVDRLKKYEAAYGK
742 KYEAAYGKQFTPCQL
759 DHANSPNKKFYQ***

Function

Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:1550553, PubMed:29915090, PubMed:30850536, PubMed:8135828, PubMed:31604922). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through cycles of four consecutive reactions (PubMed:29915090). Each beta-oxidation cycle shortens the fatty acyl-CoA by two carbons, yielding one acetyl-CoA (for the citric acid cycle), one FADH(2), and one NADH (which donate electrons to the respiratory chain for ATP production) (PubMed:29915090). These cycles repeat until the chain is fully degraded to acetyl-CoA units (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional protein--responsible for the hydration, dehydrogenation, and thiolysis steps, shows specificity for long-chain fatty acids, such as those from dietary and stored fats (PubMed:30850536, PubMed:31604922). Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA described here carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities while the trifunctional enzyme subunit beta/HADHB bears the 3-ketoacyl-CoA thiolase activity (Probable) (PubMed:29915090, PubMed:30850536, PubMed:8135828). These activities have been experimentally confirmed on a few substrates derived from beta-oxidation of long-chain saturated fatty acids such as palmitate (hexadecanoate) and laurate (dodecanoate) (PubMed:1550553, PubMed:8135828, PubMed:8163672, PubMed:8651282). In addition, based on its established catalytic mechanism, and combined genetic interaction or mutant phenotype evidence, it is predicted to act also on other substrates, including long-chain unsaturated fatty acids such as oleate (9Z-octadecenoate), linoleate (9Z,12Z-octadecadienoate), linolenate (9Z,12Z,15Z-octadecatrienoate), and others (Probable) (PubMed:26474213). Independently of subunit beta, HADHA also exhibits a cardiolipin acyltransferase activity that participates in cardiolipin remodeling; cardiolipin is a major mitochondrial membrane phospholipid (PubMed:23152787, PubMed:31604922). HADHA may act downstream of Tafazzin/TAZ, that remodels monolysocardiolipin (MLCL) to a cardiolipin intermediate, and then HADHA may continue to remodel this species into mature tetralinoleoyl-cardiolipin (PubMed:31604922). Has also been proposed to act directly on MLCL; capable of acylating MLCL using different acyl-CoA substrates, with highest activity for oleoyl-CoA (PubMed:23152787)

Protein Sequence

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

Gene Ontology

Classification GO ID Description
Cellular Component GO:0016507 mitochondrial fatty acid beta-oxidation multienzyme complex
Cellular Component GO:0005743 mitochondrial inner membrane
Cellular Component GO:0042645 mitochondrial nucleoid
Cellular Component GO:0005739 mitochondrion
Molecular Function GO:0003857 (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
Molecular Function GO:0018812 3-hydroxyacyl-CoA dehydratase activity
Molecular Function GO:0003985 acetyl-CoA C-acetyltransferase activity
Molecular Function GO:0004300 enoyl-CoA hydratase activity
Molecular Function GO:0016509 long-chain (3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
Molecular Function GO:0052816 long-chain fatty acyl-CoA hydrolase activity
Molecular Function GO:0070403 NAD+ binding
Biological Process GO:0035965 cardiolipin acyl-chain remodeling
Biological Process GO:0006635 fatty acid beta-oxidation

Reference

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[2] Hong H, Chen X, Wang H, Gu X, Yuan Y et al.. Global profiling of protein lysine lactylation and potential target modified protein analysis in hepatocellular carcinoma.. Proteomics 23(9):e2200432. 2023 May. PMID: 36625413.

[3] Lin Y, Chen M, Wang D, Yu Y, Chen R et al.. Multi-Proteomic Analysis Reveals the Effect of Protein Lactylation on Matrix and Cholesterol Metabolism in Tendinopathy.. J Proteome Res 22(6):1712-1722. 2023 Jun 2. PMID: 37159428.

[4] Yang YH, Wang QC, Kong J, Yang JT, Liu JF. Global profiling of lysine lactylation in human lungs.. Proteomics 23(15):e2200437. 2023 Aug. PMID: 37170646.

[5] Shi CM, Wang QC, Li XL, Yang YH, Tang XY et al.. Global Profiling of Protein Lactylation in Human Hippocampi.. Proteomics Clin Appl 19(2):e202400061. 2025 Mar. PMID: 39610256.

[6] He J, Lai T, Zhou Z, Yang H, Lei Z et al.. Multiomics profiling reveals the involvement of protein lactylation in nonhomologous end joining pathway conferring radioresistance in lung adenocarcinoma cell.. Sci Rep 15(1):24651. 2025 Jul 9. PMID: 40634431.

[7] Yan M, Tu H, Tang S, Gai Z, Shi Q et al.. Lactylated Proteomic Analysis Reveals Functional Implications of Lysine Lactylation In Asthenozoospermia.. Mol Cell Proteomics 24(12):101439. 2025 Dec. PMID: 41192556.

[8] Wu Q, Li Z, Gong T, Zheng X, Zhou X et al.. Porphyromonas gingivalis infection induces lysine lactylation reprogramming in human umbilical vein endothelial cells.. Front Cell Infect Microbiol 16:1706727. 2026. PMID: 41696360.