Friday, December 23, 2016

The Lyme disease spirochete lives without thiamine

Thiamine, or vitamin B1, is vital for the survival of all living things.  One of the biologically functional forms of thiamine, thiamine pyrophosphate (TPP), is essential for the catalytic activity of several critical metabolic enzymes.  For this reason, we must get thiamine from the food that we eat (or the vitamin pills that we swallow).  Microbes obtain the vitamin from their surroundings, but many can also make their own thiamine if it's not available.

It turns out that the Lyme disease spirochete Borrelia burgdorferi does not need thiamine, as described by Zhang and colleagues in Nature Microbiology.  The B. burgdorferi genome lacks the genes encoding the dedicated transporters that bring thiamine into the cell.  The genes encoding the enzymes that produce thiamine are also absent.  Chemical analysis of B. burgdorferi by HPLC failed to detect thiamine or TPP.  Despite lacking the means to make or acquire thiamine, B. burgdorferi grew just fine in culture medium devoid of thiamine.

The researchers conducted stringent tests to verify that B. burgdorferi could live without thiamine.  To remove all traces of thiamine, they introduced the bcmE gene from Clostridium botulinum into the spirochete.  The bcmE gene encodes an enzyme that rapidly breaks down thiamine.  In culture, the spirochete grew at the same rate whether or not it had bcmE.  The bcmE gene did not affect B. burgdorferi's ability to infect mice or to survive in feeding Ixodes scapularis ticks.  The results of these experiments provided strong evidence that B. burgdorferi doesn't need thiamine to infect the tick vector or mouse.

How does B. burgdorferi manage to live without thiamine?  It can do without most of the enzymes that require the TPP coenzyme, but it's less obvious how B. burgdorferi copes without pyruvate dehydrogenase (PDH), a TPP-dependent enzyme that converts pyruvate to acetyl-CoA (see figure).  Acetyl-CoA is an essential precursor to the bacterial cell wall, something that B. burgdorferi obviously needs.  The researchers proposed that B. burgdorferi makes acetyl-CoA by an alternative pathway that starts with acetate.  B. burgdorferi possesses the enzymes acetate kinase (ACK) and phosphate acetyltransferase (PTA), which convert acetate to acetyl-CoA (see figure).

Figure 4 from Zhang et al., 2016.  Enzymes in red (PDC, PDH, and POX) require the TPP coenzyme.  Metabolic pathways found in other bacteria but missing in B. burgdorferi are shown with dashed lines.

B. burgdorferi may not be alone in living without thiamine.  The researchers also looked at the genomes of other bacterial pathogens that are transmitted by arthropods.  Borrelia hermsii (relapsing fever), Rickettsia prowazekii (epidemic typhus), and R. conorii (Mediterranean spotted fever) were missing the genes for thiamine biosynthesis and the enzymes that use thiamine pyrophosphate as a coenzyme.

The presence of the alternative pathway to acetyl-CoA synthesis assumes that acetate is available in the microenvironment surrounding the arthropod-borne pathogen.  According to measurements presented in a 2010 paper, acetate is present in the midgut of fed I. scapularis ticks and in mouse blood.  The B. burgdorferi protein BBA34 may be a transporter that brings acetate into the cell.


Zhang K, Bian J, Deng Y, Smith A, Nunez RE, Li MB, Pal U, Yu AM, Qiu W, Ealick SE, & Li C (2016). Lyme disease spirochaete Borrelia burgdorferi does not require thiamin. Nature Microbiology, 2 PMID: 27869793

Xu H, Caimano MJ, Lin T, He M, Radolf JD, Norris SJ, Gherardini F, Wolfe AJ, & Yang XF (2010). Role of acetyl-phosphate in activation of the Rrp2-RpoN-RpoS pathway in Borrelia burgdorferi. PLoS pathogens, 6 (9) PMID: 20862323

Subba Raju BV, Esteve-Gassent MD, Karna SL, Miller CL, Van Laar TA, & Seshu J (2011). Oligopeptide permease A5 modulates vertebrate host-specific adaptation of Borrelia burgdorferi. Infection and immunity, 79 (8), 3407-20 PMID: 21628523

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