| NAD-malic enzyme | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 malic enzyme tetramer, Human | |||||||||
| Identifiers | |||||||||
| EC no. | 1.1.1.39 | ||||||||
| CAS no. | 9028-46-0 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
Malate dehydrogenase (decarboxylating) (EC 1.1.1.39) or NAD-malic enzyme (NAD-ME) is an enzyme that catalyzes the chemical reaction
- (S)-malate + NAD+ pyruvate + CO2 + NADH
Thus, the two substrates of this enzyme are (S)-malate and NAD+, whereas its three products are pyruvate, CO2, and NADH. Malate is oxidized to pyruvate and CO2, and NAD+ is reduced to NADH.
This enzyme belongs to the family of oxidoreductases, to be specific, those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is (S)-malate:NAD+ oxidoreductase (decarboxylating). This enzyme participates in pyruvate metabolism and carbon fixation. NAD-malic enzyme is one of three decarboxylation enzymes used in the inorganic carbon concentrating mechanisms of C4 and CAM plants. The others are NADP-malic enzyme and PEP carboxykinase.[1][2]
Fumarate signaling and mitochondrial biogenesis[edit]
Human genome encodes three different malic enzymes. ME1 is NADP-depdendent. ME2 is NAD-depdendent, while ME3 displays dual coenzyme specificity. ME2 is allosterically activated by fumarate, which is distinctive from the other two malic enzymes (ME1 and ME3). The Krebs cycle intermediate fumarate links metabolism to mitobiogenesis through binding to malic enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences. First, promoting the formation of ME2 dimers, which activate deoxyuridine 5'-triphosphate nucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA. Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1 inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemia is highly dependent on mitochondrial function and is sensitive to targeting of the fumarate-ME2 axis.[3]
References[edit]
- ^ Kanai R, Edwards, GE (1999). "3. The Biochemistry of C4 Photosynthesis". In Sage RF, Monson RK (eds.). C4 Plant Biology. pp. 43–87. ISBN 0126144400.
- ^ Christopher JT, Holtum JA (1996). "Patterns of carbon partitioning in leaves of Crassulacean acid metabolism species during deacidification". Plant Physiol. 112 (1): 393–399. doi:10.1104/pp.112.1.393. PMC 157961. PMID 12226397.
- ^ Wang YP, Sharda A, Xu SN, van Gastel N, Man CH, Choi U, Leong WZ, Li X, Scadden DT (May 2021). "Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis". Cell Metabolism. 33 (5): 1027–1041. doi:10.1016/j.cmet.2021.03.003. PMC 10472834. PMID 33770508.
