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Literature summary extracted from

  • Augoff, K.; Hryniewicz-Jankowska, A.; Tabola, R.
    Lactate dehydrogenase 5: an old friend and a new hope in the war on cancer (2015), Cancer Lett., 358, 1-7.
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
1.1.1.27 additional information direct phosphorylation of LDHA at Y10 and Y83 strongly enhances LDH-5 tetramer formation and cofactor binding, resulting in significantly increased LDH enzymatic activity Homo sapiens

Application

EC Number Application Comment Organism
1.1.1.27 diagnostics LDH levels might serve as a significant prognostic factor in high-risk patients with metastatic renal cell carcinoma (RCC) and a predictive factor associated with the response and survival benefit of the mTOR complex-1 (mTORC1) inhibitor temsirolimus. LDH is one of the risk factors included in the international prognostic index (IPI) and it is considered a strong predictor of survival of patients with aggressive lymphoid cancers. Serum LDH level inversely correlates with the survival of patients with small cell lung cancer (SCLC) and allows the selection of very high-risk patients. Serum LDH might be a useful marker for predicting global clinical outcomes in hepatocellular carcinoma patients treated with a tyrosine kinase inhibitor (sorafenib). The determination of serum LDH levels appears to be a helpful clinical tool also in the diagnosis of prostate cancer and in the control of androgenic treatment Homo sapiens
1.1.1.27 medicine LDH-5 is considered a highly promising target in cancer therapy, LDH-5 significance in the treatment and prognosis of neoplastic diseases Homo sapiens

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.1.1.27 multiple initiation sites required for transcription of the LDHA gene are identified in its promoter region, including a cAMP response element (CRE) and E-box motif. The LDHA gene promoter possesses also two conserved hypoxia response elements (HREs) containing functionally essential binding sites for hypoxia-inducible factor 1 (HIF-1) with the consensus sequence 5?-RCGTG-3?, which may strongly suggest an oxygendependent regulation of LDH-5 activity Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.1.1.27 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indol-2-carboxylic acid a N-hydroxyindole, NH1-1, and a competitive inhibitor with respect to both NADH and pyruvate Homo sapiens
1.1.1.27 3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino) benzoic acid a quinoline-3-sulfonamide, competitive inhibitor with respect to both NADH and pyruvate Homo sapiens
1.1.1.27 6-benzyl-3,4-dihydroxy-7-methyl-1-propylnaphthalene-2-carboxylic acid FX11, a competitive inhibitor with respect to both NADH and pyruvate Homo sapiens
1.1.1.27 AZ-33 a malonic derivative, a competitive inhibitor with respect to both NADH and pyruvate Homo sapiens
1.1.1.27 Chinese gall ethanol extract of the Chinese gall, commonly named Wu Bei Zi, strongly inhibits the enzyme Homo sapiens
1.1.1.27 epigallocatechin the most potent compound with anti-LDH-5 activity under both normoxia and hypoxia conditions Homo sapiens
1.1.1.27 galloflavin a blocker of LDH-5-ssDNA interactions, preventing RNA synthesis Homo sapiens
1.1.1.27 GNE-140 a piperidine derivative LDH-5 inhibitor Homo sapiens
1.1.1.27 methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indol-2-carboxylate a N-hydroxyindole, NH1-2, and a competitive inhibitor with respect to both NADH and pyruvate Homo sapiens
1.1.1.27 oxamate an inhibitor of gluconeogenesis, which suppresses cell proliferation through induction of G2/M or G0/G1 cell cycle arrest and promotion of apoptosis Homo sapiens
1.1.1.27 Spatholobus suberectus extract the extract has a strong inhibitory effect on LDH-5 expression and activity inboth estrogen-dependent and estrogen-independent human breast cancer cells Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
1.1.1.27 cytoplasm
-
 Homo sapiens 5737
-
1.1.1.27 additional information the subcellular localization of LDH-5 appears to be dependent on the phosphorylation state of Y238 Homo sapiens
-
-
1.1.1.27 nucleus
-
 Homo sapiens 5634
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.1.1.27 (S)-lactate + NAD+ Homo sapiens
-
 pyruvate + NADH + H+
-
 r

Organism

EC Number Organism UniProt Comment Textmining
1.1.1.27 Homo sapiens P00338
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
1.1.1.27 acylation lysine acetylation appears as a specific modification of LDH-5. It is involved in the control of its activity. Acetylation at Y5 decreases the LDHA protein level and inhibits LDH-5 activity. Lysine-5 acetylation reduces and be accompanied with increased LDHA protein levels in both early and late stages of pancreatic cancers. Acetylated LDHA can be recognized by a cytosolic chaperone and it is easily degraded by lysosomal proteolysis Homo sapiens
1.1.1.27 phosphoprotein LDH-5 can serve as a substrate of the oncogenic viral Src (v-Src) tyrosine kinase and the oncogenic receptor tyrosine kinase FGFR1. Direct phosphorylation of LDHA at Y10 and Y83 strongly enhances LDH-5 tetramer formation and cofactor binding, resulting in significantly increased LDH enzymatic activity. LDHA tyrosine phosphorylation also decides about the translocation of LDH-5 to the nucleus Homo sapiens

Source Tissue

EC Number Source Tissue Comment Organism Textmining
1.1.1.27 breast
-
 Homo sapiens
-
1.1.1.27 breast cancer cell
-
 Homo sapiens
-
1.1.1.27 hepatocellular carcinoma cell
-
 Homo sapiens
-
1.1.1.27 lymphoma cell
-
 Homo sapiens
-
1.1.1.27 additional information serum LDH is commonly increases in patients with hematopoietic malignancies, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, or multiplemyeloma Homo sapiens
-
1.1.1.27 pancreas
-
 Homo sapiens
-
1.1.1.27 pancreatic cancer cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.1.1.27 (S)-lactate + NAD+
-
 Homo sapiens pyruvate + NADH + H+
-
 r

Subunits

EC Number Subunits Comment Organism
1.1.1.27 tetramer LDH-5 is a LDHA tetramer Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
1.1.1.27 lactate dehydrogenase 5
-
 Homo sapiens
1.1.1.27 LDH-5
-
 Homo sapiens
1.1.1.27 LdhA
-
 Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.1.1.27 NAD+
-
 Homo sapiens
1.1.1.27 NADH
-
 Homo sapiens

Expression

EC Number Organism Comment Expression
1.1.1.27 Homo sapiens Spatholobus suberectus extract has a strong inhibitory effect on LDH-5 expression and activity inboth estrogen-dependent and estrogen-independent human breast cancer cells. Follicle-stimulating hormone, insulin, insulin-like growth factor 1, epidermal growth factor, and tumor necrosis factor alpha, are factors able to affect LDHA gene transcription through relevant intracellular signal transduction systems, including protein kinase A and C signaling pathways down

General Information

EC Number General Information Comment Organism
1.1.1.27 malfunction LDH-5 inhibitors decrease mitochondrial membrane potential and elevate intracellular oxidative stress that diminishes the ability of cells to proliferate, reduces their metastatic potential, and increases sensitivity to chemotherapeutic drugs. Inhibitors can also act as a blocker of the LDH-5–ssDNA interactions to prevent RNA synthesis. miR-34a is a direct repressor of LDHA gene expression. Inhibiting LDHA expression may reduce the invasive and metastatic potential of cancer cells by decreasing their proliferation ability and reversing their resistance to chemotherapy. Enzyme inhibitors NHI-1 and -2 used together with gemcitabine enhance the antiproliferative and anti-invasive activities of the chemotherapeutic drug, under both normoxia and hypoxia, in pancreatic ductal adenocarcinoma (PDAC) cell lines. Inhibitor NIH-2, combined with the redox-dependent bioreductive anticancer prodrug EO9, synergistically induces p53-positive cancer cell death Homo sapiens
1.1.1.27 metabolism lactate dehydrogenase-5 (LDH-5) is a central player in theWarburg effect which catalyzes the formation of lactate in the final step of the glycolytic pathway Homo sapiens
1.1.1.27 physiological function lactate dehydrogenase 5 (LDH-5) catalyzes the reduction of pyruvate by NADH to form lactate, thus determining the availability of NAD+ to maintain the continuity of glycolysis.Direct phosphorylation of LDHA at Y10 and Y83 strongly enhances LDH-5 tetramer formation and cofactor binding, resulting in significantly increased LDH enzymatic activity and promoting cancer cell metabolism and tumor growth. LDH-5 tyrosine phosphorylation might be an extra regulatory mechanism underlying the Warburg effect and lactate production. LDHA tyrosine phosphorylation decides about the translocation of LDH-5 to the nucleus, where it acts as a single-stranded DNA-binding protein, stimulating transcription and/or DNA replication. LDH-5 plays a crucial role in tumor maintenance and elevated LDHA gene expression characterizes many human tumors Homo sapiens