Riboswitches regulate the synthesis of proteins and are controlled by related compounds such as thiamine pyrophosphate.[1] They are usually found within non-coding portions of messenger RNAs.[1]Thiamine pyrophosphate is also known as TPP. TPP is essential in all three domains of life, including: bacteria, fungi, and plants. [1] They use this specific riboswitch to control genes that are in charge of synthesizing thiamine and any phosphorylated derivatives.[1]TPP and its riboswitch work together to directly regulate the synthesis of a proteins related to TPP. [1]Thiamine pyrophosphate is the most widely distributed riboswitch of the metabolite-sensing RNA regulatory system. [1] The reason for this is because TPP is a form of vitamin B1, and vitamin B1 takes an essential part in many protein-catalyzed reactions; thus it is used quite often.
Function
The function of this particular riboswitch does not depend on the transcription process. [2] The riboswitch predominantly folds into the on state, whether TPP is present or not. [2] Meanwhile, the off state aptamer structure does not appear during transcription. [2] However, the transition from the on state to the aptamer structure is extremely slow and because of this, thiamine pyrophosphate has the chance to interact with the RNA before full formation of the aptamer structure, prompting the switch to flip. [2] Conformational rearrangements are induced by the binding of TPP to the riboswitch, leading to the overall stabilization of the RNA fold.[1] Without TPP alternative conformations are adopted, opening the Shine-Dalgarno sequence for ribosome binding in the on state.[1]
Interesting Information
RNA does not recognize the central thiazole moiety, this explains why the antimicrobial PTPP (pyrithiamine pyrophosphate) targets this particular riboswitch and down regulates the expression of thiamine metabolic genes.[1] The secondary and tertiary structure elements that are harnessed by the riboswitch are stabilized by the natural ligand and its drug-like analogue.[1] Recent research has found that the antimicrobial compound PTPP can turn off the expression of critical biosynthetic genes, by binding to bacterial and fungal TPP riboswitches.[1] The loss of PTPP activity, along with drug-resisting mutations in TPP riboswitches, might be due to the disruption of specific tertiary contacts made by tetrads .[1]
Structural Highlights
TPP riboswitches were one of the first of several classes found to form successful interactions with negatively charged phosphate groups.[1]
TPP's pyrophosphate group is bound by a pair of Mg2+ ions, . [1] TPP's terminal phosphate group is coordinately bonded to both , but the thiazole-linked phosphate is only coordinately bonded to Mg2.[1]
Holding Mg1 in place are and they can be found within the region that previously was known for pyrophosphate recognition.[1] Structures of proteins bound to TPP typically position Mg2+, Ca2+, or Mn2+ ions using charged amino acids, in a site equivalent.[1] However, the TPP riboswitch is the only riboswitch that contains the Mg1 ion.[1] A bivalent cation allows TPP to reach into the pyrophosphate-binding pocket.[1] This in turn stabilizes the important tertiary interactions that are required for gene regulation, and supporting the use of Mg2+ for TPP binding in both bacterial and eukaryotic TPP riboswitches.[1]
