P23368 (MAOM_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
NAD-dependent malic enzyme, mitochondrial
Short name=NAD-ME
EC=1.1.1.38

Alternative name(s):
Malic enzyme 2

Gene names

Name:

ME2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	584 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)

Catalytic activity	(S)-malate + NAD+ = pyruvate + CO2 + NADH.
Cofactor	Divalent metal cations. Prefers magnesium or manganese.
Enzyme regulation	Subject to allosteric activation by fumarate.
Subunit structure	Homotetramer. Ref.8 Ref.9
Subcellular location	Mitochondrion matrix.
Miscellaneous	This isoenzyme can also use NADP+ but is more effective with NAD+.
Sequence similarities	Belongs to the malic enzymes family.

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Polymorphism
Domain	Transit peptide
Ligand	Metal-binding NAD
Molecular function	Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Allosteric enzyme Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	malate metabolic process Inferred from electronic annotation. Source: InterPro
Cellular component	mitochondrial matrix Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	NAD binding Inferred from electronic annotation. Source: InterPro electron carrier activity Traceable author statement Ref.1. Source: UniProtKB malate dehydrogenase (decarboxylating) activity Traceable author statement. Source: ProtInc malate dehydrogenase (oxaloacetate-decarboxylating) activity Inferred from electronic annotation. Source: EC metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 18

18

Mitochondrion Ref.4

Chain

19 – 584

566

NAD-dependent malic enzyme, mitochondrial

PRO_0000018537

Regions

Nucleotide binding

165 – 173

9

NAD

Nucleotide binding

311 – 328

18

NAD

Sites

Active site

112

1

Proton donor

Active site

183

1

Proton acceptor

Metal binding

255

1

Divalent metal cation

Metal binding

256

1

Divalent metal cation

Metal binding

279

1

Divalent metal cation

Binding site

67

1

Allosteric activator

Binding site

91

1

Allosteric activator

Binding site

165

1

Substrate

Binding site

259

1

NAD

Binding site

421

1

Substrate

Binding site

466

1

Substrate

Site

279

1

Important for activity By similarity

Amino acid modifications

Modified residue

156

1

N6-acetyllysine Ref.5

Modified residue

224

1

N6-acetyllysine Ref.5

Modified residue

240

1

N6-acetyllysine Ref.5

Modified residue

272

1

N6-acetyllysine Ref.5

Modified residue

346

1

N6-acetyllysine Ref.5

Natural variations

Natural variant

114

1

P → L.
Corresponds to variant rs16952692 [ dbSNP | Ensembl ].

VAR_034104

Natural variant

450

1

G → E.
Corresponds to variant rs649224 [ dbSNP | Ensembl ].

VAR_050017

Experimental info

Mutagenesis

67

1

R → S: Abolishes activation by fumarate. Ref.9

Mutagenesis

91

1

R → T: Abolishes activation by fumarate. Ref.9

Secondary structure

1

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584

Helix Strand Turn

Details...

Helix

27 – 30

4

Turn

32 – 34

3

Helix

37 – 39

3

Helix

42 – 47

6

Turn

51 – 53

3

Helix

61 – 72

12

Helix

78 – 88

11

Turn

89 – 91

3

Helix

93 – 102

10

Helix

104 – 111

8

Helix

115 – 126

12

Beta strand

132 – 136

5

Helix

137 – 139

3

Helix

143 – 147

5

Beta strand

157 – 161

5

Beta strand

163 – 166

4

Turn

167 – 169

3

Helix

173 – 177

5

Helix

178 – 191

14

Helix

195 – 197

3

Beta strand

198 – 205

8

Helix

210 – 213

4

Helix

229 – 246

18

Beta strand

251 – 254

4

Helix

259 – 269

11

Turn

270 – 272

3

Beta strand

273 – 277

5

Helix

278 – 298

21

Helix

302 – 304

3

Beta strand

307 – 310

4

Helix

314 – 328

15

Turn

329 – 331

3

Helix

334 – 338

5

Beta strand

341 – 345

5

Turn

360 – 362

3

Helix

363 – 365

3

Helix

377 – 384

8

Beta strand

387 – 391

5

Helix

401 – 410

10

Beta strand

415 – 418

4

Helix

423 – 425

3

Helix

430 – 436

7

Turn

437 – 439

3

Beta strand

442 – 447

6

Helix

467 – 469

3

Helix

471 – 480

10

Helix

488 – 499

12

Helix

504 – 508

5

Helix

516 – 518

3

Helix

519 – 536

18

Helix

549 – 555

7

Sequences

	Sequence		Length	Mass (Da)
	P23368 [UniParc]. Last modified November 1, 1991. Version 1. Checksum: 4CEF9AF89B07D93D	FASTA	584	65,444
	10 20 30 40 50 60 MLSRLRVVST TCTLACRHLH IKEKGKPLML NPRTNKGMAF TLQERQMLGL QGLLPPKIET 70 80 90 100 110 120 QDIQALRFHR NLKKMTSPLE KYIYIMGIQE RNEKLFYRIL QDDIESLMPI VYTPTVGLAC 130 140 150 160 170 180 SQYGHIFRRP KGLFISISDR GHVRSIVDNW PENHVKAVVV TDGERILGLG DLGVYGMGIP 190 200 210 220 230 240 VGKLCLYTAC AGIRPDRCLP VCIDVGTDNI ALLKDPFYMG LYQKRDRTQQ YDDLIDEFMK 250 260 270 280 290 300 AITDRYGRNT LIQFEDFGNH NAFRFLRKYR EKYCTFNDDI QGTAAVALAG LLAAQKVISK 310 320 330 340 350 360 PISEHKILFL GAGEAALGIA NLIVMSMVEN GLSEQEAQKK IWMFDKYGLL VKGRKAKIDS 370 380 390 400 410 420 YQEPFTHSAP ESIPDTFEDA VNILKPSTII GVAGAGRLFT PDVIRAMASI NERPVIFALS 430 440 450 460 470 480 NPTAQAECTA EEAYTLTEGR CLFASGSPFG PVKLTDGRVF TPGQGNNVYI FPGVALAVIL 490 500 510 520 530 540 CNTRHISDSV FLEAAKALTS QLTDEELAQG RLYPPLANIQ EVSINIAIKV TEYLYANKMA 550 560 570 580 FRYPEPEDKA KYVKERTWRS EYDSLLPDVY EWPESASSPP VITE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human NAD(+)-dependent mitochondrial malic enzyme. cDNA cloning, primary structure, and expression in Escherichia coli." Loeber G., Infante A.A., Maurer-Fogy I., Krystek E., Dworkin M.B. J. Biol. Chem. 266:3016-3021(1991) [PubMed: 1993674] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[2]	"Physical and transcriptional map of a 311-kb segment of chromosome 18q21, a candidate lung tumor suppressor locus." Yanaihara N., Kohno T., Takakura S., Takei K., Otsuka A., Sunaga N., Takahashi M., Yamazaki M., Tashiro H., Fukuzumi Y., Fujimori Y., Hagiwara K., Tanaka T., Yokota J. Genomics 72:169-179(2001) [PubMed: 11401430] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 37-80.
[3]	Abts H. Thesis (1995), University of Cologne, Germany Cited for: NUCLEOTIDE SEQUENCE OF 421-584. Tissue: B-cell.
[4]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed: 12665801] [Abstract] Cited for: PROTEIN SEQUENCE OF 19-33. Tissue: Platelet.
[5]	"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-156; LYS-224; LYS-240; LYS-272 AND LYS-346, MASS SPECTROMETRY.
[6]	"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: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]	"Crystal structure of human mitochondrial NAD(P)(+)-dependent malic enzyme: a new class of oxidative decarboxylases." Xu Y., Bhargava G., Wu H., Loeber G., Tong L. Structure 7:877-889(1999) [PubMed: 10467136] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
[8]	"Structure of a closed form of human malic enzyme and implications for catalytic mechanism." Yang Z., Floyd D.L., Loeber G., Tong L. Nat. Struct. Biol. 7:251-257(2000) [PubMed: 10700286] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 21-584 IN COMPLEX WITH NAD; DIVALENT METAL ION AND SUBSTRATE ANALOG, HOMOTETRAMERIZATION.
[9]	"Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate." Yang Z., Lanks C.W., Tong L. Structure 10:951-960(2002) [PubMed: 12121650] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 20-573 IN COMPLEX WITH ATP; MANGANESE; ALLOSTERIC ACTIVATOR AND SUBSTRATE ANALOG, MUTAGENESIS OF ARG-67 AND ARG-91, HOMOTETRAMERIZATION.
[10]	"Crystal structures of substrate complexes of malic enzyme and insights into the catalytic mechanism." Tao X., Yang Z., Tong L. Structure 11:1141-1150(2003) [PubMed: 12962632] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 21-584 IN COMPLEX WITH SUBSTRATE; NAD; MANGANESE AND ALLOSTERIC ACTIVATOR, ENZYME MECHANISM.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M55905 mRNA. Translation: AAA36197.1.
AB045122 Genomic DNA. Translation: BAB40980.1.
AJ294818 mRNA. Translation: CAC14574.1.

IPI

IPI00011201.

PIR

A39503.

RefSeq

NP_002387.1. NM_002396.4.

UniGene

Hs.233119.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DO8	X-ray	2.20	A/B/C/D	21-584	[»]
1EFK	X-ray	2.60	A/B/C/D	1-584	[»]
1EFL	X-ray	2.60	A/B/C/D	1-584	[»]
1GZ3	X-ray	2.30	A/B/C/D	20-573	[»]
1GZ4	X-ray	2.20	A/B/C/D	23-573	[»]
1PJ2	X-ray	2.30	A/B/C/D	21-584	[»]
1PJ3	X-ray	2.10	A/B/C/D	21-584	[»]
1PJ4	X-ray	2.30	A/B/C/D	21-584	[»]
1PJL	X-ray	2.90	A/B/C/D/E/F/G/H	1-584	[»]
1QR6	X-ray	2.10	A/B	1-584	[»]

ProteinModelPortal

P23368.

SMR

P23368. Positions 21-573.

ModBase

Search...

Protein-protein interaction databases

STRING

P23368.

PTM databases

PhosphoSite

P23368.

Polymorphism databases

DMDM

126733.

Proteomic databases

PeptideAtlas

P23368.

PRIDE

P23368.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000321341; ENSP00000321070; ENSG00000082212.

GeneID

4200.

KEGG

hsa:4200.

UCSC

uc002ley.1. human.

Organism-specific databases

CTD

4200.

GeneCards

GC18P048405.

H-InvDB

HIX0014451.

HGNC

HGNC:6984. ME2.

HPA

HPA008247.
HPA008880.

MIM

154270. gene.

neXtProt

NX_P23368.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG14338.

GeneTree

ENSGT00390000000754.

HOGENOM

HBG289821.

HOVERGEN

HBG000746.

InParanoid

P23368.

OMA

QALRFHR.

OrthoDB

EOG402WRR.

PhylomeDB

P23368.

Gene expression databases

ArrayExpress

P23368.

Bgee

P23368.

CleanEx

HS_ME2.

Genevestigator

P23368.

GermOnline

ENSG00000082212. Homo sapiens.

Family and domain databases

InterPro

IPR015884. Malic_enzyme_CS.
IPR012301. Malic_N.
IPR012302. Malic_NAD-bd.
IPR001891. Malic_OxRdtase.
IPR016040. NAD(P)-bd_dom.
[Graphical view]

Gene3D

G3DSA:3.40.50.10380. G3DSA:3.40.50.10380. 1 hit.
G3DSA:3.40.50.720. NAD(P)-bd. 1 hit.

KO

K00027.

Pfam

PF00390. malic. 1 hit.
PF03949. Malic_M. 1 hit.
[Graphical view]

PIRSF

PIRSF000106. ME. 1 hit.

PRINTS

PR00072. MALOXRDTASE.

SMART

SM00919. Malic_M. 1 hit.
[Graphical view]

PROSITE

PS00331. MALIC_ENZYMES. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00157. NADH.

NextBio

16554.

SOURCE

Search...

Entry information

Entry name

MAOM_HUMAN

Accession

Primary (citable) accession number: P23368
Secondary accession number(s): Q9BYG1, Q9H4B2

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1991
Last sequence update:	November 1, 1991
Last modified:	January 25, 2012
This is version 135 of the entry and version 1 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.