Asukamycin

1. Discovery, producing organism1) and structure2,3)
Asukamycin was isolated from the culture broth of Streptomyces nodosus strain AM-1042T andrecognized as an antibiotic. Asukamycin is related to the manumycin group antibiotics because itcontains a multifunctional mC7N unit as its central structural element, but has a naturally uniquemono-substituted cyclohexane.
OO

HNR
O
H
N

HOO

Asukamycin

Streptomyces nodosus.
subsp. asukaensis AM-1042TOHOR=
CH3 CH3 CH3Manumycin ACH3R=

2. Physical data1)
Yellow needles. C31H34 N2O7; mol wt 546.24. Sol. in DMSO, MeOH, acetone; Insol. in H2O, hexane.
3. Biological activity1)
The manumycin group antibiotics exhibit antibacterial activity against Gram-positive bacteria. In
particular, asukamycin was found to have anticoccidial activity. These compounds are known toinhibit the protein farnesyltransferase4).
Antimicrobial spectrum of asukamycin

Test organism		
Staphylococcus aureus FDA209 JC-1
Staphylococcus aureus FDA209
Staphylococcus aureus FS-1277*
Staphylococcus aureus KB-64**
Staphylococcus albus
Bacillus subtilis PCI 219
Bacillus subtilis ATCC6633
Bacillus megaterium APF
Bacillus anthracis
Bacillus cereus T
Bacillus agri
Micrococcus luteus PCI1001
Micrococcus flavus 16
Corynebacterium paurometabolum
Nocardia asteroides
Micobacterium smegmatis ATCC607
Escherichia coli NIHJ
Klebsiella pneumoniae PCI602
Salmonella typhimurium
Shigella sonnei E-33
Pseudomonas aeruginosa P-3* resistant to penicillin** resistant to tetracycline and erythromycin

MIC (µg/ml)
0.78
3.12
6.25
6.25
12.5
3.12
6.25
6.25
12.5
3.12
12.5
6.25
1.56
1.56
1.56>100
100>100>100>100>100

4. Biosynthesis5-16)
The central and multifunctional mC7N unit typical of this group of antibiotics serves as the starting unit for a short polyketide chain. It is biosynthesized from a C4 Krebs cycle and a C3 triose
phosphate pool, and is recognized to intermediate by a pathway distinct in nature from the shikimate, polyketide, or pentose phosphate routes leading to other mC7N units.
The C5 unit arises from a novel intermoleculular cyclization of 5-amino-levulinic acid, and acyclohexane ring and the adjacent carbon arises from the seven carbon atoms of shikimic acid.
The side chains represent typical polyketide-derived moieties, differing with respect to their
combinations of starter and elongation units.
The biosynthetic gene cluster for asukamycin was identified. The biosynthetic pathway andtranscriptional regulation were proposed.
OH
OH

O
COSCoA

O

OH
O

OH

HO

CH2OH

CH2OH

COOH

NH

COOH

COOH

H 3C

H+
N
OP–O
OH

OH
NH2O

CH2OH

O

COOH

NH

CH2OH

CH2OH

COOH

CHO

O

NH2O

OH
COSCoA

COSCoA

NH2O

H+N–O
H +N

COSCoA

O

H +N
HOH
O

PLP-enzyme

H 3C

OH
NH2NH2O

HOCOOH

OHOH
O

OH
NHO

H
O

H3C
OP–O

OH–HO

H +N

O

H
NOP
H
O

PLP-enzyme

O

Asukamycin
Manumycin

OH
NH2O

NH2O

OH
COSCoANH2O
COSCoA

Proposed pathway for assembly of mC7N units7)

HOO

Asukamycin

Model for assembly of C5N units
in asukamycin biosynthesis7)

5. References
1. [112] S. Ōmura et al., J. Antibiot. 29, 876-881 (1976)
2. [160] K. Kakinuma et al., J. Am. Chem. Soc. 101, 3402-3404 (1979)
3.		
H. Cho et al., J. Org. Chem. 58, 7925-7928 (1993)
4.		
M. Hara et al., Proc. Natl Acad. Sci. USA 90, 2281-2285 (1993)
5. [444] R. Thiericke et al., J. Am. Chem. Soc. 112, 3979-3987 (1990)
6. [334] A. Nakagawa et al., J. Chem. Soc. Chem. Commun. 519-521 (1985)
7. [398] J. M. Beale et al., J. Am. Chem. Soc. 110, 4435-4437 (1986)
8.		
K. Petrícková et al., Chembiochem. 15, 1334-1345 (2014)
9.		
T. Ito, Yakugaku Zasshi 133, 1007-1015 (2013)
10.		
Z. Rui et al., Chem. Biol. 20, 879-887(2013)
11.		
L. Bai, Chem. Biol. 20, 859-860 (2013)12.		
P. Xie et al., Appl. Microbiol. Biotechnol. 96, 451-460 (2012)
13.		
S. Pospíšil et al., J. Appl. Microbiol. 111, 1116-1128 (2011)
14.		
Z. Rui et al., J. Biol. Chem. 285, 24915-24924 (2010)15.		
M. Petrícek et al., J. Bacteriol. 188, 5113-5123 (2006)
16.		
Y. Hu & H. G. Floss, J. Am. Chem. Soc. 126, 3837-3844 (2004)