Tautomycetin is a natural product first isolated from ''Streptomyces griseochromogenes'', a bacterium found in the soil of the Zhejiang Province, China. It was also later found in ''Penicillium urticae''. It is a linear polyketide very similar in structure to

tautomycin Tautomycin is a chemical that occurs naturally in shellfish and is produced by the bacterium ''Streptomyces spiroverticillatus''. It is a polyketide-based structure characterized by a three hydroxyl groups, two ketones, a dialkylmaleic anhydride, ...

, both of which contain a unique dialkylmaleic anhydride moiety, which is essential for their pharmacological activity. Tautomycetin is a selective inhibitor of protein phosphatase 1. __TOC__

Biosynthesis

Much of the biosynthesis of tautomycetin has been deduced. It is synthesized in ''S. griseochromogenes'' by two type I polyketide synthases, denoted by modules named TtnA and TtnB. After initial loading with

acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

, four methylmalonyl-CoAs and three

malonyl-CoA Malonyl-CoA is a coenzyme A derivative of malonic acid. Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis. Fatty acid biosynthesis Malonyl-CoA provides 2-carbon units to fatty acids and commi ...

s are added alternately by sequential Claisen condensation, followed by one ethylmalonyl-CoA. Each ketone of the incorporated acetate group is selectively modified by a ketoreductase (KR), dehydratase (DH), or enoylreductase (ER) as indicated. The dialkyl maleic anhydride moeity is synthesized separately by eight enzymes (TtnKLMNOPRS) and incorporated into the growing polyketide by esterification mediated via TtnK at the end of TtnA. The polyketide is released from TtnB, by a thioesterase TtnB-TE and undergoes oxidation at the C6 position, catalyzed by the enzyme TtnI. Finally, this intermediate undergoes an enzyme-catalyzed decarboxylation-dehydration to form the final compound, tautomycetin. The total synthesis of tautomycetin has been reported.

Pharmacology

Tautomycetin has been shown to have antibiotic and antifungal activities. It has also been identified as a potent protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) inhibitor with IC50 values as low as 0.21 nM and 0.94 nM respectively, the lowest of over 40 natural product phosphatase inhibitors. In addition, tautomycetin is a potent T cell-specific immunosuppressor and has been investigated for treatment in grafting and transplantation. It has useful anticancer properties, inducing apoptosis through the inhibition of several protein cascades in colorectal cancer and thyroid cancer.

References

{{reflist Polyketides Polyketide antibiotics