Suppression of the human malic enzyme 2 modifies energy metabolism and inhibits cellular respiration.

ABSTRACT: Human mitochondrial NAD(P)⁺-dependent malic enzyme (ME2) is well-known for its role in cell metabolism, which may be involved in cancer or epilepsy. We present potent ME2 inhibitors based on cyro-EM structures that target ME2 enzyme activity. Two structures of ME2-inhibitor complexes demonstrate that 5,5'-Methylenedisalicylic acid (MDSA) and embonic acid (EA) bind allosterically to ME2's fumarate-binding site. Mutagenesis studies demonstrate that Asn35 and the Gln64-Tyr562 network are required for both inhibitors' binding. ME2 overexpression increases pyruvate and NADH production while decreasing the cell's NAD⁺/NADH ratio; however, ME2 knockdown has the opposite effect. MDSA and EA inhibit pyruvate synthesis and thus increase the NAD⁺/NADH ratio, implying

SUBMITTER: Hsieh JY 

PROVIDER: S-EPMC10202922 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature