• Biotechnology and Bioprocess Engineering:BBE
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• v.9 no.3
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• pp.171-178
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• 2004

Glucose alone was found to be the most effective carbon source for producing compactin. An initial glucose concentration of 40 g/L gave the highest compactin concentration of 250mg/L. Among the various nitrogen sources, when 5g/L of pharmamedia and soybean meal as the sole nitrogen source were used, respectively, the compactin concentration was higher than 250mg/L. Especially, in the case of the mixture of 6 g/L of pharmamedia and 8 g/L of soybean meal, the compactin concentration was 400mg/L. To select the best surfactant for effective compactin production, various surfactants were investigated. When Triton X-100 was used, the maximum compactin concentration was 445mg/L. With the initial concentration ranging from 1.5 to 2.0 g/L, the compactin concentration was the highest at 465-450mg/L. The cell concentration was similar to that of the control without the addition of Triton X-100. On the other hand, when the above 4.0 g/L of Triton X-100 were used, the cell concentration decreased. Using the based results, the continuous fed-batch cultures by adding the Triton X-100 were carried out for 10 days in an air-lift bioreactor. When 1.5 g/L of Triton X-100 was added to the culture broth at 0, 4, and 8 days of culture, respectively, the compactin production was increased with the increase of culture time. The maximum compactin concentration after 10days of culture was 1,200mg/L, which was about 2.0-fold higher than that of the control without the addition of Triton X-100.

• Journal of Microbiology and Biotechnology
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• v.19 no.7
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• pp.690-697
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• 2009

In the present study, production of compactin by Penicillium brevicompactum WA 2315 was studied. In the first step, various precultural parameters were studied by substituting one factor at a time. Subsequently, the effect of maltodextrin DE 18 on compactin production was studied. The optimized parameters gave maximum compactin production of 850 ${\mu}g/gds$as compared with 678 ${\mu}g/gds$before optimization. Statistical study was performed to further improve the production and develop a robust model. An improved yield of 950 ${\mu}g/gds$was obtained using the conditions proposed by the experimental model. The present study emphasizes the importauce of precultural and nutritional parameters on the production of compactin, and further confirms the usefulness of solid-state fermentation for the production of industrially important secondary metabolites. It also confirms that complex nitrogen sources such as oil cakes can be used for the production of compactin.

• Journal of Microbiology and Biotechnology
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• v.27 no.5
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• pp.956-964
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• 2017

Compactin and pravastatin are competitive cholesterol biosynthesis inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and belong to the statin drugs; however, the latter shows superior pharmacokinetic characteristics. Previously, we reported that the bacterial P450, CYP105D7, from Streptomyces avermitilis can catalyze the hydroxylation of 1-deoxypentalenic acid, diclofenac, and naringenin. Here, we demonstrate that CYP105D7 could also catalyze compactin hydroxylation in vitro. In the presence of both bacterial and cyanobacterial redox partner systems with an NADPH regeneration system, the reaction produced two hydroxylated products, including pravastatin (hydroxylated at the C6 position). The steady-state kinetic parameters were measured using the redox partners of putidaredoxin and its reductase. The $k_m$ and $k_{cat}$ values for compactin were $39.1{\pm}8.8{\mu}M$ and $1.12{\pm}0.09min^{-1}$, respectively. The $k_{cat}/K_m$ value for compactin ($0.029min^{-1}{\cdot}{\mu}M^{-1}$) was lower than that for diclofenac ($0.114min^{-1}{\cdot}{\mu}M^{-1}$). Spectroscopic analysis showed that CYP105D7 binds to compactin with a $K_d$ value of $17.5{\pm}3.6{\mu}M$. Molecular docking analysis was performed to build a possible binding model of compactin. Comparisons of different substrates with CYP105D7 were conclusively illustrated for the first time.

• Archives of Pharmacal Research
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• v.14 no.2
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• pp.143-146
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• 1991

A new synthetic sequence for the chiral lactone moiety of compactin was developed from $\alpha$-D-glucose in 9 steps via simultaneous reductive detosylation and epoxide-ring opening of 2, 3-epoxy-4-tosylate using NaBH_4$ to afford 2, 4-dideoxy sugar as a key intermediate.

• Food Engineering Progress
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• v.13 no.4
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• pp.243-250
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• 2009

Pravastatin sodium, competitive inhibitors of HMG-CoA(3-hydroxy-3-methylglutaryl coenzyme A) reductase, is produced from the culture broth of Streptomyces carbophilus KCCM 10370, The production of Pravastatin sodium was increased about 45 fold compared to wild type by UV mutation. Production of Pravastatin was also improved by continuous feeding of Compactin sodium to 24% and bioconversion ratio was also increased to 4.3% by intermittent addition. In main culture, concentration of Compactin sodium was kept less than 0.1%(w/v) under continuous feeding of Compactin sodium then product was 0.49% and bioconversion was 70%. After finishing the fermentation, Pravastatin was purified by various chromatographies such as Diaion HP20 resin column, Partition, and ODS(Octa-Decylsilyl Silicagel) resin column with a final yield of 70~72% and over 99.7% purity. The IR, UV, and NMR study of the purified Pravastatin sodium showed the same pattern as that of EP(European Pharmacopoeia).

• Journal of Microbiology and Biotechnology
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• v.11 no.6
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• pp.1011-1017
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• 2001

Streptomyces sp. Y-110 cytochrome P-450, induced by the addition of compactin -Na into the culture medium, was purified from the cell extract to apparent homogeniety, mainly by DEAE-Sepharose, hydroxyapatite, and Mono Q column chromatyography. The sepcific activity of purified enzyme on its substrate, compactin-Na, was determined to be 15 nmol of pravastatin per mg protein. The molecular mass of this enzyme on SDS-PAGE was $37{\pm}0.5$ kDa, pI was 4.5, and its CO difference spectrum showed maximum absorption peaks at 452 and 550nm, respectively. The N-terminal amino acid sequence was determined to be Met>Thr>Cys>Thr>Pro>Val>Thr>Val>The>Gly>Ala>Ala>Gly>Gln>Ile>Gly>Tyr>Ala>Leu. Its apparent $K_m$ on compactin-Na was $1.294{\mu}M{\cdot}min^-1,\;and\;V_{max}\;was\;1.028{\mu}M{\cdot}min^-1$. The maximum substrate concentration ($K_s$) for reaction was $270 {\mu}M$and thus $1/[K_s]$ was $3.7{\mu}M$. These physicochemical characteristics and kinetic behavior of this enzyme were compared and shown to be different from those of Streptomyces cytochrome P-450 enzymes reported, suggesting that this enzyme may be an additional member of the Streptomyces cytochrome P-450 family.

• Microbiology and Biotechnology Letters
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• v.28 no.5
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• pp.291-297
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• 2000

A strain producing high levels of compaction was isolated from soil and identified as Penicillium sp. Y-8515 based on the morphological characteristics and ribosomal RNA sequence analysis. Optimization of several different carbon and nitrogen sources for the effective production of compaction was performed resulting in the medium compositions containing 5%(w/v) glucose, 1.0 % soybean meal, 0.5% yeast extract, 0.5%(NH$_4$)$_2$$SO_4$, 0.25%,$ NaH_2$$PO_4$, 0.25% $CaCO_3$. The fixed con-centration of glucose(5%, w/v) and relatively lower concentrations(less than 2.5%, w/v) of soybean meal stimu-lated the transformation of the growth morphology from filamentous to pellet form. Comparing to that by filamentous form, the production of compactin by pellet form increased up to 1.5 folds. In a fed-batch fermentation, continuous feeding of the mixture of glucose and nitrogen source at the ratio of 10:1 showed 3.5-fold more produc-tion yield of compaction comparing to the batch mode.

• Archives of Obesity and Metabolism
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• v.1 no.1
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• pp.14-25
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• 2022

In 1971, Dr. Akira Endo succeeded in isolating a cholesterol synthesis inhibitor, compactin. Later, compactin was renamed mevastatin, meaning that it stops the synthesis of mevalonate, which is considered the first statin. However, mevastatin is not commercially released, whereas lovastatin, developed by Alfred Albert of Merk in 1979, was the first commercially developed statin. After the 4S study, the first largescale clinical trial with statins conducted in Scandinavia showed a dramatic secondary preventive effect against cardiovascular disease, and the effectiveness of statins in patients with dyslipidemia was repeatedly demonstrated. Subsequently, many oral drugs that affect blood lipid concentration; statins and ezetimibe aimed at reducing low-density lipoprotein (LDL)) cholesterol; fibrates and omega 3 formulations aimed at reducing triglycerides were widely developed and used in Korea. In this article, we review the results of clinical studies on representative cardiovascular diseases for four types of oral drugs for dyslipidemia, which are currently the most commonly used in Korea.