生物谷报道：RNA控制元素是一种RNA片段。研究人员在2007年1月号的《自然—化学生物学》上报告说，与RNA控制元素相连结的小分子可能代表了一种全新的抗菌药靶标。
作为RNA的小片段，RNA控制元素在细菌代谢物出现时能控制基因的表达。赖氨酸是细菌的一种关键氨基酸，赖氨酸RNA控制元素控制了赖氨酸的生物合成。 Ronald Breaker和同事创建了化学性质类似于赖氨酸的小分子。他们发现部分这种氨酸类似物与赖氨酸RNA控制元素结合在一起，结果阻止了赖氨酸的生物合成，从而阻止了细菌的生长。
RNA控制元素可感知许多关键细菌的代谢。作者从理论上推测，以RNA控制元素为靶标也许可提供一种新型的抗菌药。
(a) The sequence and secondary structure model of the repressed-state lysC 5' UTR from B. subtilis. Red nucleotides are conserved in at least 90% of the representatives identified by bioinformatics (Supplementary Figs. 1 and 2). The putative antiterminator hairpin that forms in the absence of ligand is shaded blue. An additional 63 nucleotides (not shown) reside between nucleotide 268 and the lysC start codon. A 179-nucleotide construct (179 lysC) spanning nucleotides 27 through 205 (bracketed) was used to determine ligand binding affinities. Nucleotides for which spontaneous cleavage activity changes upon ligand binding are circled (regions A, B and C) and correspond to the bands identified in Figure 2b. (b) The lysine biosynthesis pathway in B. subtilis. The name of the gene that codes for the enzyme or transporter at each step is indicated adjacent to a solid arrow. The expression of aspartokinase II and a lysine-specific importer (lysC and yvsH, boxed) is regulated by a lysine riboswitch in the 5' UTR of each gene. IUPAC numbering for each carbon atom of lysine is shown. The lysine analog AEC (boxed), which differs from lysine in that C4 is replaced by sulfur, is also shown.
原文出处：
Nat.Chem.Bio January 2007, Volume 3 Number 1 pp1-68
Antibacterial lysine analogs that target lysine riboswitches pp44 - 49
Kenneth F Blount, Joy Xin Wang, Jinsoo Lim, Narasimhan Sudarsan and Ronald R Breaker
Published online: 03 December 2006 | doi:10.1038/nchembio842
First paragraph | Full Text | PDF (345K) | Supplementary information
See also: News and Views by Lea & Piccirilli
作者简介：
Ronald Breaker, Ph.D.
Henry Ford II Professor of Molecular, Cellular and Developmental Biology, HHMI Investigator
Email: ronald.breaker@yale.edu
Room: KBT 452
Phone: 432-9389/432-6554
Web site
B.S. University of Wisconsin-Stevens Point 1987; Ph.D. Purdue University 1992
Ongoing investigations into the mechanisms of cellular life are revealing the details of many biological processes including information transfer, catalysis, signal transduction and molecular recognition. The fundamental roles of nucleic acids in the process of information transfer have been well established. However, the participation of RNA and DNA in other critical biochemical processes only now is becoming clearer. A significant advance in this area of research has been the discovery that RNA, like proteins, can function as an enzyme and catalyze chemical reactions. Ribozymes also may have played a critical role in the origin and evolutionary progression of life during the ?NA world? when an early metabolic state is believed to have been guided entirely by enzymes made of RNA. The sophistication of these primitive ribozymes and of modern ribozymes is defined by the structural and functional versatility of nucleic acids, and these parameters have yet to be fully explored.
We are probing the structural and catalytic repertoire of nucleic acids by using in vitro evolution? method by which rare RNAs or DNAs with new and improved functions can be isolated from pools of mutagenized or random-sequence molecules. In vitro evolution is modeled after the process of Darwinian evolution and is composed of iterative cycles of selection and amplification at the molecular level. Individual RNA or DNA molecules that display the desired phenotype are selected and subsequently amplified by chemical or enzymatic means. In related efforts, we are pioneering methods for the modular rational design of RNA and DNA enzymes that have new or improved catalytic function. For example, both modular rational design and in vitro evolution methods have been used to create a variety of allosteric ribozymes. These RNA-based molecular switches can be engineered to undergo activation or deactivation in the presence of small organic compounds, heavy metals, or even light.
The similarity in chemical structure between RNA and DNA had posed an important question: Can single-stranded DNA molecules, like proteins and RNA, assume distinct secondary and tertiary structures that function as catalysts? We have addressed this question by successfully screening a pool of 10 trillion different DNAs for molecules that catalyze their own self-destruction or the destruction of other target DNA molecules. In addition, we have created examples of DNA enzymes that use amino acids as cofactors, thereby demonstrating that nucleic acid enzymes can make use of the same chemical moieties used by proteins for the formation of enzyme active sites. Most recently, we have created a series of DNA enzymes that catalyze the reactions typically used for DNA cloning. We are continuing to define the catalytic potential of both RNA and DNA under physiological conditions and to explore the range of chemical reactions that can be catalyzed by novel nucleic acid enzymes when they are created outside the physical confines and conditions of the cell.
Selected Publications
N. Carmi, S. Balkhi and R. R. Breaker (1998) Cleaving DNA with DNA. Proc. Natl Acad. Sci. USA 95:2233-2237.
Y. Li and R. R. Breaker (1999) Phosphorylating DNA with DNA. Proc. Natl. Acad. Sci. USA 96: 2746-2751.
G. Soukup and R. R. Breaker (1999) Engineering Precision RNA Molecular Switches. Proc. Natl. Acad. Sci. USA 96:3584-3589.
M. Koizumi, G. A. Soukup, J. Q. Kerr and R. R. Breaker (1999) Allosteric selection of ribozymes that respond to the second messengers cGMP and cAMP. Nature Struct. Biol. 6:1062-1071.
