Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.

https://www.pnas.org/content/pnas/77/7/3957.full.pdf

Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.

Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth

A number of glycoproteins have oligosaccharides linked to protein in a GlcNAc----asparagine bond. These oligosaccharides may be either of the complex, the high-mannose or the hybrid structure. Each type of oligosaccharides is initially biosynthesized via lipid-linked oligosaccharides to form a Glc3Man9GlcNAc2-pyrophosphoryl-dolichol and transfer of this oligosaccharide to protein. The oligosaccharide portion is then processed, first of all by removal of all three glucose residues to give a Man9GlcNAc2-protein. This structure may be the immediate precursor to the high-mannose structure or it may be further processed by the removal of a number of mannose residues. Initially four alpha 1,2-linked mannoses are removed to give a Man5 - GlcNAc2 -protein which is then lengthened by the addition of a GlcNAc residue. This new structure, the GlcNAc- Man5 - GlcNAc2 -protein, is the substrate for mannosidase II which removes the alpha 1,3- and alpha 1,6-linked mannoses . Then the other sugars, GlcNAc, galactose, and sialic acid, are added sequentially to give the complex types of glycoproteins. A number of inhibitors have been identified that interfere with glycoprotein biosynthesis, processing, or transport. Some of these inhibitors have been valuable tools to study the reaction pathways while others have been extremely useful for examining the role of carbohydrate in glycoprotein function. For example, tunicamycin and its analogs prevent protein glycosylation by inhibiting the first step in the lipid-linked pathway, i.e., the formation of Glc NAc-pyrophosphoryl-dolichol. These antibiotics have been widely used in a number of functional studies. Another antibiotic that inhibits the lipid-linked saccharide pathway is amphomycin, which blocks the formation of dolichyl-phosphoryl-mannose. In vitro, this antibiotic gives rise to a Man5GlcNAc2 -pyrophosphoryl-dolichol from GDP-[14C]mannose, indicating that the first five mannose residues come directly from GDP-mannose rather than from dolichyl-phosphoryl-mannose. Other antibodies that have been shown to act at the lipid-level are diumycin , tsushimycin , tridecaptin, and flavomycin. In addition to these types of compounds, a number of sugar analogs such as 2-deoxyglucose, fluoroglucose , glucosamine, etc. have been utilized in some interesting experiments. Several compounds have been shown to inhibit glycoprotein processing. One of these, the alkaloid swainsonine , inhibits mannosidase II that removes alpha-1,3 and alpha-1,6 mannose residues from the GlcNAc- Man5GlcNAc2 -peptide. Thus, in cultured cells or in enveloped viruses, swainsonine causes the formation of a hybrid structure.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibitors of the Biosynthesis and Processing of N-Linked Oligosaccharide Chains

https://www.jstage.jst.go.jp/article/antibiotics1968/29/12/29_12_1346/_pdf

Ml-236a, ml-236b, and ml-236c, new inhibitors of cholesterogenesis produced by penicillium citrinum

Inhibitors of the biosynthesis and processing of n-linked

The structure of compactin (I){7-[1,2,6,7,8,8a-hexahydro-2-methyl-8-(2-methylbutyryloxy)naphthyl]-3-hydroxyheptan-5-olide}, a metabolite isolated from cultures of Penicillium brevicompactum, has been determined by a combination of spectroscopic, chemical, and X-ray crystallographic methods.

Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum

The structure of clavulanic acid, a β-lactamase inhibitor isolated from Streptomyces clavuligerus, has been shown by spectroscopic methods and X-ray analysis to be a novel fused β-lactam.

Clavulanic acid, a novel β-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis

The structures of two new, naturally occurring β-lactams are proposed on the basis of spectroscopic properties, and their interconversion.

Structures of olivanic acid derivatives MM 4550 and MM 13902; two new, fused β-lactams isolated from Streptomyces olivaceus

The synthesis of the unsymmetrical biphenyls 10 and 25 has been carried out by the palladium(0) catalysed coupling of the aryl boronic acid derivatives 5 and 20 with the aryl bromides 9 and 23 derived from (R)-4-hydroxyphenylglycine and (S)-tyrosine. In the former case unsuccessful attempts were made to bring about cyclization to compound 4 which is an analogue of the biphenyl ring system found in vancomycin. In the latter case, a variety of cyclization methods were used to give the cyclic products 34 and 35 which are analogues of the biphenomycin antibiotics.

Application of the Suzuki biphenyl synthesis to the natural products biphenomycin and vancomycin

Two new β-lactams have been isolated from strains of Serratia and Erwinia sp. and identified as (3R, 5R)- and (3S, 5R)-carbapenam-S-carboxylic acid. These novel carbapenams lack antibacterial activity, are resistant to both β-lactamases I and II from Bacillus cereus and are not detected by the lactamase induction assay. Radiolabelled and stable isotope experiments have established that both metabolites together with the antibiotic 5R-carbapenem-3-carboxylic acid are glutamate and acetate derived. A number of possible pathways for the biosynthesis of these compounds as well as their relationship to the more complex members of the carbapenem family of β-lactam antibiotics are discussed.

The biosynthetic implications of acetate and glutamate incorporation into (3R,5R)-carbapenam-3-carboxylic acid and (5R)-carbapen-2-em-3-carboxylic acid by Serratia sp.

Allan G. Brown

Papers

Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium brevicompactum

Clavulanic acid, a novel β-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis

Structures of olivanic acid derivatives MM 4550 and MM 13902; two new, fused β-lactams isolated from Streptomyces olivaceus

Application of the Suzuki biphenyl synthesis to the natural products biphenomycin and vancomycin

The biosynthetic implications of acetate and glutamate incorporation into (3R,5R)-carbapenam-3-carboxylic acid and (5R)-carbapen-2-em-3-carboxylic acid by Serratia sp.