TOWARD NOVEL LANTIBIOTICS
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NEWS OF THE WEEK BIOCHEMISTRY TOWARD NOVEL LANTIBIOTICS Enzyme may allow engineering of new antibiotics for food preservation C HEMISTS AT THE UNIVER- sity of Illinois, Urbana- Champaign, have isolated and purified the bacterial enzyme responsible for turning a small .-Lys ^Gly Gty Ser Gly Val- "ίο H / N -y CH3 HN His ~Glu Met' Asn Asn-NH ψ s^VvS" Trp -Gln- Ph ' e ^Val NH / -Phe T H R E E - R I N G P E P T I D E Lacticin 481 contains three rings, two lanthionine-containing ones (green) and a single methyllanthionine-containing one (red). It also contains an unusual dehydrated threonine (blue). peptide into lacticin 481, a mem- ber of the class of potent antibi- otics known as lantibiotics. Although the genes encoding lan- tibiotic biosynthetic enzymes have been known for a long time, this is the first time that one of these enzymes has been purified in its active form. "The isolation of this enzyme opens the door to possible gen- eration of new lantibiotics with different or improved activities," notes chemistJohn C. Vederas of the University of Alberta. Lacticin 481 is produced by a strain of Lactococcus lactis, a bac- terium used in cheese produc- tion. Other lantibiotics are used as natural preservatives in a vari- ety of foods, including milk, meat, and canned vegetables. Un- like many antibiotics used as pharmaceuticals, lantibiotics have been used for half a centu- ry in more than 40 countries without any significant signs of ENERGY POLICY Chemical CEOs Protest Natural Gas Prices C hief executives from the nation's 19 largest chemical companies have written President George W. Bush and con- gressional leaders, asking that the government curb high natural gas prices. The CEOs urge the gov- ernment to adopt a national program to raise energy effi- ciency, reduce natural gas use for electricity, increase drilling, and expand tax re- lief for gas producers. The chemical industry has been hard hit by high gas prices because it uses gas as fuel and feedstock and is the U.S.'s leading gas consumer. The CEOs say today's high prices come when national gas inventories are at record highs—9% above the five-year average. The CEOs blame the government, charging that its environmental policies have spurred greater gas use for electricity generation. However, natural gas use by electric utilities over the past several years has been flat or declining, according to Energy Department figures, and its analysts note that even if gas prices drop, chemical companies will still be in trouble. Utilities have indeed in- stalled more clean-burning, efficient natural-gas-fired turbines over the past decade. However, high gas prices have led utilities to burn cheaper fuel, mainly coal, while waiting for the price of gas to decline. The analysts argue that high gas prices are likely to fall later this year, but they also warn that with cheaper prices, utilities will fire up now-idle gas turbines, leading to more demand, price volatility, and a new round of price spikes.— JEFF JOHNSON lantibiotic-resistant bacteria popping up. Lantibiotics are peptide-based compounds produced by bacteria that live on lactic acid. They are characterized by the presence of rings formed by two unusual dou- ble-headed amino acids—lan- thionine and methyllanthionine— that contain thioether bridges. The small enzyme LctM, which does the lion's share of synthe- sizing lacticin 481, was purified at Illinois by Lili Xie, Wilfred A. van der Donk, and their col- leagues [Science, 303,679 (2004)}. With the help of chemist Neil L. Kelleher, the team used mass spectrometry to prove that the purified enzyme performs a care- fully controlled sequence of re- actions on the linear, unmodified peptide precursor of lacticin 481. The team found that LctM first dehydrates four specific ser- ine and threonine residues in the peptide precursor. The enzyme then catalyzes the attack by cys- teine side chains on three of these dehydrated residues, yielding a peptide containing a methyllan- thionine-based ring and two lan- thionine-based ones as well as a single dehydrated threonine residue. A different enzyme then trims a bit off the end of the pep- tide precursor to produce mature, active lacticin 481. Remarkably, LctM can per- form its string of dehydrations and cyclizations even on versions oflacticin 481 precursor peptides that are truncated or that contain different peptide subunits. "LctM's flexibility suggests that it can be used with semisynthetic sub- strate peptides to create new lac- ticin analogs," van der Donk tells C&EN. The team also hopes to learn more about how LctM catalyzes these reactions, van der Donk says. "It will be fascinating to learn in the future how the LctM enzyme recognizes its substrate in three dimensions and the de- tailed mechanisms of these trans- formations," Vederas adds.— AMANDAYARNELL 10 C&EN / FEBRUARY 2, 2004 HTTP://WWW.CEN-ONLINE.ORG
Transcript of TOWARD NOVEL LANTIBIOTICS
NEWS OF THE WEEK
B I O C H E M I S T R Y
TOWARD NOVEL LANTIBIOTICS Enzyme may allow engineering of new antibiotics for food preservation
CHEMISTS AT THE UNIVER-sity of Illinois, Urbana-Champaign, have isolated
and purified the bacterial enzyme responsible for turning a small
. - Lys ^Gly
Gty
Ser
Gly
V a l -
"ίο H /N-y
CH3
HN
His
~Glu
Met ' Asn
Asn-NH ψ s^VvS" T r p - G l n - P h ' e
^Val NH /
-Phe
T H R E E - R I N G P E P T I D E Lacticin 481 contains three rings, two lanthionine-containing ones (green) and a single methyllanthionine-containing one (red). It also contains an unusual dehydrated threonine (blue).
peptide into lacticin 481, a member of the class of potent antibiotics known as lant ibiot ics . Although the genes encoding lan-
tibiotic biosynthetic enzymes have been known for a long time, this is the first time that one of these enzymes has been purified in its active form.
"The isolation of this enzyme opens the door to possible generation of new lantibiotics with different or improved activities," notes chemist John C. Vederas of the University of Alberta.
Lacticin 481 is produced by a strain of Lactococcus lactis, a bacterium used in cheese production. Other lantibiotics are used as natural preservatives in a variety of foods, including milk, meat, and canned vegetables. Unlike many antibiotics used as pharmaceuticals, lantibiotics have been used for half a century in more than 40 countries without any significant signs of
E N E R G Y P O L I C Y
Chemical CEOs Protest Natural Gas Prices
Chief executives from the nation's 19 largest chemical companies
have written President George W. Bush and congressional leaders, asking that the government curb high natural gas prices.
The CEOs urge the government to adopt a national program to raise energy efficiency, reduce natural gas use for electricity, increase drilling, and expand tax relief for gas producers.
The chemical industry has been hard hit by high gas prices because it uses gas as fuel and feedstock and is the
U.S.'s leading gas consumer. The CEOs say today's high
prices come when national gas inventories are at record highs—9% above the five-year average. The CEOs blame the government, charging that its environmental policies have spurred greater gas use for electricity generation.
However, natural gas use by electric utilities over the past several years has been flat or declining, according to Energy Department figures, and its analysts note that even if gas prices drop, chemical companies wil l still be in trouble.
Utilities have indeed installed more clean-burning, efficient natural-gas-fired turbines over the past decade. However, high gas prices have led utilities to burn cheaper fuel, mainly coal, while waiting for the price of gas to decline.
The analysts argue that high gas prices are likely to fall later this year, but they also warn that with cheaper prices, utilities wi l l fire up now-idle gas turbines, leading to more demand, price volatility, and a new round of price spikes.— JEFF JOHNSON
lantibiotic-resistant bacteria popping up.
Lantibiotics are peptide-based compounds produced by bacteria that live on lactic acid. They are characterized by the presence of rings formed by two unusual double-headed amino acids—lan-thionine and methyllanthionine— that contain thioether bridges.
The small enzyme LctM, which does the lion's share of synthesizing lacticin 481, was purified at Illinois by Lili Xie, Wilfred A. van der Donk, and their colleagues [Science, 303,679 (2004)}. With the help of chemist Neil L. Kelleher, the team used mass spectrometry to prove that the purified enzyme performs a carefully controlled sequence of reactions on the linear, unmodified peptide precursor of lacticin 481.
The team found that LctM first dehydrates four specific serine and threonine residues in the peptide precursor. The enzyme then catalyzes the attack by cysteine side chains on three of these dehydrated residues, yielding a peptide containing a methyllan-thionine-based ring and two lan-thionine-based ones as well as a single dehydrated threonine residue. A different enzyme then trims a bit off the end of the peptide precursor to produce mature, active lacticin 481.
Remarkably, LctM can perform its string of dehydrations and cyclizations even on versions of lacticin 481 precursor peptides that are truncated or that contain different peptide subunits. "LctM's flexibility suggests that it can be used with semisynthetic substrate peptides to create new lacticin analogs," van der Donk tells C&EN.
The team also hopes to learn more about how LctM catalyzes these reactions, van der Donk says. "It will be fascinating to learn in the future how the LctM enzyme recognizes its substrate in three dimensions and the detailed mechanisms of these transformations," Vederas adds.— AMANDAYARNELL
10 C&EN / FEBRUARY 2, 2004 H T T P : / / W W W . C E N - O N L I N E . O R G
