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Nature © Macmillan Publishers Ltd 1997

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580 NATURE

VOL 390

11 DECEMBER 1997

Genomic sequence of a

Lyme disease spirochaete,

Borrelia burgdorferi

Claire M. Fraser*, Sherwood Casjens†, Wai Mun Huang†, Granger G. Sutton*, Rebecca Clayton*, Raju Lathigra‡, Owen White*,

Karen A. Ketchum*, Robert Dodson*, Erin K. Hickey*, Michelle Gwinn*, Brian Dougherty*, Jean-Francois Tomb*,

Robert D. Fleischmann*, Delwood Richardson*, Jeremy Peterson*, Anthony R. Kerlavage*, John Quackenbush*,

Steven Salzberg*, Mark Hanson‡, Rene van Vugt†, Nanette Palmer†, Mark D. Adams*, Jeannine Gocayne*, Janice Weidman*,

Teresa Utterback*, Larry Watthey*, Lisa McDonald*, Patricia Artiach*, Cheryl Bowman*, Stacey Garland*, Claire Fujii*,

Matthew D. Cotton*, Kurt Horst*, Kevin Roberts*, Bonnie Hatch*, Hamilton O. Smith*& J. Craig Venter*

*The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 20850, USA

†Division of Molecular Biology and Genetics, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84132, USA

‡MedImmune, Inc., 35 West Watkins Mill Road, Gaithersburg, Maryland 20878, USA

…………………………………………………………………………………………………………………………………………………………….…………………………………………………………….

The genome of the bacterium Borrelia burgdorferi B31, the aetiologic agent of Lyme disease, contains a linear

chromosome of 910,725 base pairs and at least 17 linear and circular plasmids with a combined size of more than

533,000 base pairs. The chromosome contains 853 genes encoding a basic set of proteins for DNA replication,

transcription, translation, solute transport and energy metabolism, but, like Mycoplasma genitalium, it contains no

genes for cellular biosynthetic reactions. Because B. burgdorferi and M. genitalium are distantly related eubacteria,

we suggest that their limited metabolic capacities reflect convergent evolution by gene loss from more metabolically

competent progenitors. Of 430 genes on 11 plasmids, most have no known biological function; 39% of plasmid genes

are paralogues that form 47 gene families. The biological significance of the multiple plasmid-encoded genes is not

clear, although they may be involved in antigenic variation or immune evasion.

In the mid-1970s, a geographic clustering of an unusual rheumatoid

arthritis-like condition was reported in Connecticut1. That cluster

of cases focused attention on the syndrome that is now called Lyme

disease. It was subsequently realized that a similar disorder had been

known in Europe since the beginning of this century. Lyme disease is

characterized by some or all of the following manifestations: an

initial erythematous annular rash, ’flu-like symptoms, neurological

complications, and arthritis in about 50% of untreated patients2.In

the United States, the disease occurs primarily in northeastern and

midwestern states, and in western parts of California and Oregon.

These regions coincide with the ranges of various species of Ixodes

ticks, the primary vector of Lyme disease. Lyme disease is now the

most common tick-transmitted illness in the United States, and

has been reported in many temperate parts of the Northern

Hemisphere.

It was not until the early 1980s that a new spirochaete, Borrelia

burgdorferi3, was isolated and cultured from the midgut of Ixodes

ticks, and subsequently from patients with Lyme disease4,5. Analysis

of genetic diversity among individual Borrelia isolates has defined a

closely related cluster containing at least 10 tick-borne species of

Lyme disease agents, called ‘B. burgdorferi (sensu lato)’. B. burgdor–

feri resembles most other spirochaetes in that it is a highly

specialized, motile, two-membrane, spiral-shaped bacterium that

lives primarily as an extracellular pathogen. Borrelia is fastidious

and difficult to culture in vitro, requiring a specially enriched media

and low oxygen tension6.

One of the most striking features of B. burgdorferi is its unusual

genome, which includes a linear chromosome approximately one

megabase in size7–10 and numerous linear and circular plasmids11–13,

with some isolates containing up to 20 different plasmids. The

plasmids have a copy number of approximately one per chromo-

some10,14, and different plasmids often appear to share regions of

homologous DNA13,15,16. Long-term culture of B. burgdorferi results

in the loss of some plasmids, changes in protein expression profiles,

and a loss in the ability of the organism to infect laboratory animals,

suggesting that the plasmids encode important proteins involved in

virulence17–19.

Because of its importance as a pathogen of humans and animals,

and the value of complete genome sequence information for under–

standing its life cycle and advancing drug and vaccine development,

we sequenced the genome of B. burgdorferi type strain (B31), using

the random sequencing method previously described20–24.Herewe

summarize the results from sequencing, assembly and analysis of

the linear chromosome and 11 plasmids.

Chromosome analysis

The linear chromosome of B. burgdorferi has 910,725 base pairs (bp)

and an average G+C content of 28.6%. Base pair one represents the

first double-stranded base pair that we observed at the left telomere.

Previous genome characterizations agree with the nucleotide

sequence of the large chromosome10,25–28. The 853 predicted

coding sequences (open reading frames; ORFs) have an average

size of 992 bp, similar to that observed in other prokaryotic

genomes, with 93% of the B. burgdorferi genome representing

Figure 1 Linear representations of the B. burgdorferi B31 chromosome and

plasmids. The location of predicted coding regions colour-coded by biological

role, RNA genes, and tRNAs is indicated. Arrows represent the direction of

transcription for each predicted coding region. Numbers associated with tRNA

symbols represent the number of tRNAs at a locus. Numbers associated with

GES represent the number of membrane-spanning domains according to the

Goldman, Engelman and Steitz scale as calculated by TopPred49. Only proteins

with five or more GES are indicated. Members of paralogous gene families are

identified by family number. Transporter abbreviations: mal, maltose; P, gly and

bet, proline, glycine, betaine; glyc, glycerol; aa, amino acid; E, glutamate; fru,

fructose; glu, glucose; s/p, spermidine/putrescine; pan, pantothenate; Pi, phos-

phate; lac, lactate; rib, ribose; ?, unknown.

Nature © Macmillan Publishers Ltd 1997

articles

NATURE

VOL 390

11 DECEMBER 1997 581

coding sequence. Biological roles were assigned to 59% of the 853

ORFs using the classification scheme adapted from Riley29 (Fig. 1),

12% of ORFs matched hypothetical coding sequences of unknown

function from other organisms, and 29% were new genes. The

average relative molecular mass (M

) of the chromosome-encoded

proteins in B. burgdorferi is 37,529 ranging from 3,369 to 254,242,

values similar to those observed in other bacteria including

Haemophilus influenzae20 and Mycoplasma genitalium21. The

median isoelectric point (pI) for all predicted proteins is 9.7.

Analysis of codon usage in B. burgdorferi reveals that all 61 triplet

codons are used. When both AU- and GC-containing codons

specify a single amino acid, there is a marked bias (from 2-fold to

more than 20-fold, depending on the amino acid) in the use of AU-

rich codons. The most frequently used codons are AAA (Lys, 8.1%),

AAU (Asn, 5.9%), AUU (Ile, 5.9%), UUU (Phe, 5.7%), GAA (Glu,

5.0%), GAU (Asp, 4.2%) and UUA (Leu, 4.2%). The most common

amino acids are Ile (10.6%), Leu (10.3%), Lys (10.2%), Ser (7.8%)

and Asn (7.2%). The high value for Lys is in agreement with the

median calculated isoelectric point of 9.7.

Plasmid analysis

Analysis of the nucleotide sequence and Southern analyses on B.

burgdorferi DNA indicate that, in addition to the large linear

chromosome, isolate B31 contains linear plasmids of the following

approximate sizes: 56 kilobase pairs (kbp) (lp56), 54 kbp (lp54),

four plasmids of 28 kbp (lp28-1, lp28-2, lp28-3 and lp28-4), 38 kbp

(lp38), 36 kbp (lp36), 25 kbp (lp25) and 17 kbp (lp17); and circular

plasmids of the following sizes: 9 kbp (cp9), 26 kbp (cp26) and five

or six homologous plasmids of 32 kbp (cp32). These include all of

the plasmids previously identified in this strain, but comparisons

with other B31 cultures suggest that this isolate may have lost one 21

kbp linear and one or two 32 kbp circular plasmids during growth in

culture since its original isolation11–14,19,30. The sequences of all

plasmids were assembled as part of this project. However, the

assembled sequences of the cp32 and related lp56 plasmids could

not be determined with a high degree of confidence because of DNA

sequence similarity among them ($99% in several regions of

3,000–5,000 bp per plasmid)13,16 (Table 1). Improved assembly

strategies are being tested to achieve closure on these plasmids

(G. Sutton, unpublished). Plasmid lp17 is identical to that of lp16.9

from Barbour et al.15.

The 11 plasmids we have described contain a total of 430 putative

ORFs with an average size of 507 bp; plasmid G+C content ranges

from 23.1% to 32.3%. Only 71% of plasmid DNA represents

predicted coding sequences, a value significantly lower than that

on the chromosome. This indicates that average intergenic distances

are greater in the plasmids than in the chromosome, and that many

potential ORFs contain authentic frameshifts or stops (see E29, for

example), suggesting that they are decaying genes not encoding

functional proteins. Of the 430 plasmid ORFs, only 70 (16%) could

be identified and these include membrane proteins such as OspA-D,

decorin-binding proteins, the VlsE lipoprotein recombination cas-

sette, and the purine ribonucleotide biosynthetic enzymes GuaA

and GuaB. We found that 100 ORFs (23%) match other hypothe-

tical proteins from plasmids in this and related strains of B.

burgdorferi 15,16,31; 10 ORFs (2.3%) match hypothetical proteins

from species other than Borrelia; and 250 ORFs (58%) have no

database match.

We found that 47 paralogous gene families containing from 2 to

12 members account for 39% (169 ORFs) of the plasmid-encoded

genes with no known biological role (Fig. 1). Paralogue families 32

and 50, typified by previously identified B. burgdorferi plasmid

genes cp32 orfC and cp8.3 orf2, respectively, have some similarities

to proteins involved in replication, segregation and control of copy

number in other bacterial systems16,31. Previous studies have

reported examples of plasmid gene duplication, but the extent of

Table 2 Gene identification numbers are listed with the prefix BB as in Fig. 2. Each gene

identified is listed in its functional role category (adapted from Riley29). The percentage of

similarity and a two-letter abbreviation for genus and species for the best match are also

shown. An expanded version of this table with additional information is available on the

World-Wide Web at http://www.tigr.org/tdb/mdb/bbdb/bbdb.htm. Abbreviations of gene

names are: Ac, acetyl; BP, binding protein; biosyn, biosynthesis; cello, cellobiose; CPDase,

carboxypeptidase; Dcase, decarboxylase; DHase, dehydrogenase; flgr, flagellar/flagellum;

fru, fructose; GBP, glycine, betaine, L-proline; glu, glucose; Kase, kinase; mal, maltose; MC-

methyl-accepting chemotaxis; MTase, methyltransferase; NAG, N-acetylglucosamine; OH,

hydroxy; OP, oligopeptide; P, phosphate; PPTase, phosphotransferase; PPase, phospha-

tase; prt, protein; put, putative; RDase, reductase; RG, ribose/galactose; SAM, S-adenosyl-

methionine; Sase, synthetase/synthase; SP, spermidine/putrescine; ss, single-stranded;

sub, subunit; Tase, transferase.

Abbrevation of genus and species are: Ah, Aeromonas hydrophila; Ar, Agrobacterium

radiobacter; Al, Alteromonas sp.; Ab, Anabaena sp.; An, Anacystis nidulans; At, arabidopsis

thaliana; Av, Azotobacter vinelandii; Bf, Bacillus firmus; Bl, Cacillus licheniformis; Bm,

Bacillus megaterium; Bs, Bacillus stearothermophilus; Bs, Bacillus subtilis; Bb, Borrelia

burgdorferi; Bc, Borrelia coriaceae; Bh, Borrelia hermsii; Ba, Buchnera aphidicola; Ca,

Clostridium acetobutylicum; Cl, Clostridium longisporum; Cp, Clostridium perfringens; Cg,

Corynegacterium glutamicum; Cb, Coxiella burnetii; Cp, Cyanophora paradoxa; Dd,

Dictyostelium discoideum; Ec, Escherichia coli; Eh, Entamoeba histolytica; Ec,

Enterobacter cloacae; El, Enterococcus faecalis; Eh, Enterococcus hirae; Ha,

Haemophilus aegyptius; Hi, Haemophilus influenzae; Hp, Helicobacter pylori; Hs, Homo

sapiens; La, Lactobacillus acidophilus; Ll, Lactococcus lactis; Li, Leptospira interrogans

serovar lai; Mj, Methanococcus jannaschii; Mb, Methanosarcina barkeri; Ml,

Mycobacterium leprae; Mt, Mycobacterium tuberculosis; Mc, Mycoplasma capricolum;

Mg, Mycoplasma genitalium; Mh, Mycoplasma hominis; Mh, Mycoplasma hyorhinis; Mm,

Mycoplasma mycoides; Mp, Mycoplasma pneumoniae; Mx, Myxococcus xanthus; Ng,

Neisseria gonorrhoeae; Nm, Neisseria meningitidis; Os, Odontella sinensis; Pt,

Paramecium tetraurelia; Pa, Pediococcus acidilactici; Pf, Plasmodium falciparum; Pg,

Porphyromonas gingivalis; Pv, Proteus vulgaris; Pa, Pseudomonas aeruginosa; Pm,

Pseudomonas mevalonii; Pp, Pseudomonas putida; Rm, Rhizobium meliloti; Rc,

Rhodobacter capsulatus; Rs, Rhodobacter sphaeroides; Rp, Rickettsia prowazekii; Sc,

Saccharomyces cerevisiae; Sc, Salmonella choleraesius; St, Salmonella typhimurium; Sh,

Serpulina hyodysenteriae; Sd, Shigella dysenteriae; So, Spinacia oleracea; Sc,

Staphylococcus camosus; Se, Staphylococcus epidermidis; Sp, Streptococcus pyogen-

es; Sc, Streptomyces coelicolor; Ss, Sulfolobus solfataricus; Syn, Synechococcus sp.; Sp,

Synechocystis PCC6803; Tt, Thermoanaerobacterium thermosaccharolyticum; Tb, Ther-

mophilic bacterium RT8.B4.; Ttv, Thermoproteus tenax virus; Tm, Thermotoga maritima; Tat,

Thermus aquaticus thermophilus; Ta, Thermus aquaticus; Td, Treponema denticola; Tp,

Treponema pallidum; Ta, Triticum aestivum; Tb, Trypanosoma brucei mitochondrion; Vc,

Vibrio cholerae; Vp, Vibrio parahaemolyticus; Zm, Zymomonas mobilis.

Table 1 Genome features in Borrelia burgdorferi

Chromosome 910,725 bp (28.6% G+C)

Coding sequences (93%)

RNAs (0.7%)

Intergenic sequence (6.3%)

853 coding sequences

500 (59%) with identified database match

104 (12%) match hypothetical proteins

249 (29%) with no database match

………………………………………………………………………….…………………………………………………………………………….

Plasmids

cp9 9,386 bp (23.6% GC)

cp26 26,497 bp (26.3% GC)

lp17 16,828 bp (23.1% GC)

lp25 24,182 bp (23.3% GC)

lp28-1 26,926 bp (32.3% GC)

lp28-2 29,771 bp (31.5% GC)

lp28-3 28,605 bp (25.1% GC)

lp28-4 27,329 bp (24.4% GC)

lp36 36,834 bp (26.8% GC)

lp38 38,853 bp (26.1% GC)

lp54 53,590 bp (28.1% GC)

Coding sequences (71%)

Intergenic sequence (29%)

430 coding sequences

70 (16%) with identified database match

110 (26%) match hypothetical proteins

250 (58%) with no database match

………………………………………………………………………….…………………………………………………………………………….

Ribosomal RNA Chromosome coordinates

16S 444581–446118

23S 438590–441508

5S 438446–438557

23S 435334–438267

5S 435201–435312

………………………………………………………………………….…………………………………………………………………………….

Stable RNA

tmRNA 46973–47335

mpB 750816–751175

………………………………………………………………………….…………………………………………………………………………….

Transfer RNA

34 species (8 clusters,14 single genes)

………………………………………………………………………….…………………………………………………………………………….

*The telomeric sequences of the nine linear plasmids assembled as part of this study were

not determined; estimation of the number of missing terminal nucleotides by restriction

analysis suggests that less than 1,200 bp is missing in all cases. Comparisons with

previously determined sequences of lp 16.9 and one terminus of lp28-1 indicate that 25,

60 and 1,200 bp are missing, respectively.

Nature © Macmillan Publishers Ltd 1997

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582 NATURE

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this redundancy has become even more apparent with the complete

sequence of these 11 plasmids from isolate B31. Moreover, a

preliminary search of 221 putative ORFs from the cp32s and lp56

indicates that at least 50% display $70% amino-acid similarity to

ORFs from the other 11 plasmids presented here (data not shown).

Although plasmid-encoded genes have been implicated in infectiv-

ity and virulence17–19, the biological roles of most of these genes are

not known. The significance of the large number of paralogous

plasmid-encoded genes is not understood. These proteins may

be expressed differentially in tick and mammalian hosts, or may

undergo homologous recombination to generate antigenic varia-

tion in surface proteins. This hypothesis is supported by the

identification of 63 plasmid-encoded putative membrane lipopro-

teins (Fig. 1).

Several copies of a putative recombinase/transposase similar to

IS891-like transposases were identified in the B. burgdorferi plas-

mids. Linear plasmid 28-2 contains one full-length copy of this

gene. Although no inverted repeats were found on either side of the

transposase, there is a putative ribosome-binding site several

nucleotides upstream of the apparent start codon, and a stem–

loop structure (−27 kcal mol

−1

) 195 bp downstream of the stop

codon in an area with no ORFs. This transposase might represent a

functional gene important for the frequent DNA rearrangements

that presumably occur in Borrelia plasmids. There are other partial

or nearly complete copies of the transposase gene that contain

frame-destroying mutations elsewhere in the genome: two copies on

lp17, one on lp36, one on lp38, one on lp28-3, two on lp28-1, and

one near the right end of the large linear chromosome.

Origin of replication

The replication mechanism for the linear chromosome and plas-

mids in B. burgdorferi is not yet known. Replication possibly begins

at the termini, as has been proposed for the poxvirus hairpin

telomeres32, or may begin from a single origin somewhere along

the length of the linear replicon. Of the genes on the linear

chromosome, 66% are transcribed away from the centre of the

chromosome (Fig. 1), similar to the transcriptional bias observed

for the genomes of M. genitalium21 and M. pneumoniae33. It has

been suggested that bacterial genes are optimally transcribed in the

same direction as that in which replication forks pass over them,

particularly for highly transcribed genes34,35

Given the transcriptional bias observed in B. burgdorferi, it seems

likely that the origin of replication is near the centre of the

chromosome. Because bacterial chromosomal replication origins

are usually near dnaA36, it is intriguing to note that this gene

(BB437) lies almost exactly at the centre of the linear B. burgdorfer-

ichromosome10,27. A centrally initiated, bi-directional replication

fork would be equidistant from the two chromosome ends, and

replication would traverse the rRNA genes in the same direction as

transcription.

An analysis of GC skew, (G 2C)/(G þC) calculated in 10-kilo-

base (kb) windows across the chromosome, shows a clear break at

the putative origin of replication. The GC-skew values are uni-

formly negative from 0 to 450 kb (minus strand), and uniformly

positive (plus strand) from 450 kb to the end of the chromosome

(Fig. 2). Additional evidence for the location of the origin of

replication comes from our discovery of an octamer, TTGTTTTT,

whose skewed distribution in the plus versus the minus strand of the

chromosome matches the GC skew (Fig. 2). The biological sig-

nificance of this octamer has not yet been determined, although it

may be analogous to the Chi site in Escherichia coli that is implicated

in recBCD mediated recombination. No GC skew was observed in

any of the plasmids, although the heptamer ATTTTTT displays a

skewed distribution in the plus versus the minus strand of lp28-4

that changes at the approximate midpoint of the plasmid (not

shown).

Transcription and translation

Genes encoding the three subunits (a,b,b9) of the core RNA

polymerase were identified in B. burgdorferi along with j

and two

alternative jfactors, j

and rpoS. The role and specificity of each of

these jfactors in transcription regulation in B. burgdorferi are not

known. The nusA,nusB and rho genes, which are involved in

transcription elongation and termination, were also identified.

A region of the genome with a significantly higher G þC content

(43%), located between nucleotides 434,000 and 447,000, contains

the rRNA operon. As previously reported, the rRNA operon in B.

burgdorferi contains a 16S rRNA–Ala-tRNA–Ile-tRNA–23S

rRNA–5S rRNA–23S rRNA–5S rRNA37,38. All of the genes are

present in the same orientation, except for that encoding Ile

tRNA. Four unrelated genes, encoding 3-methyladenine glycosylase,

hydrolyase and two with no database match, are also present in the

rRNA operon. Three of these genes are transcribed in the same

direction as the rRNAs.

We identified in the chromosome 31 tRNAs with specificity for all

20 amino acids (Fig. 1). These are organized into 7 clusters plus 13

single genes. All tRNA synthetases are present except glutaminyl

tRNA-synthetase. A single glutamyl tRNA synthetase probably

aminoacylates both tRNA

Glu

and tRNA

Gln

with glutamate followed

by transamidation by Glu-tRNA amidotransferase, a heterotrimeric

enzyme present in B. burgdorferi and several Gram-positive bacteria

and archaea30. The lysyl-tRNA synthetase (LysS) in B. burgdorferi is a

class I type that has no resemblance to any known bacterial or

eukaryotic LysS, but is most similar to LysS from the archaea40.

Replication, repair and recombination

The complement of genes in B. burgdorferi involved in DNA

replication is smaller than in E. coli, but similar to that in M.

genitalium21. Three ORFs have been identified with high homology

to four of the ten polypeptides in the E. coli DNA polymerase III: a,

band g, and t.InE. coli, the gand tproteins are produced by

programmed ribosomal frameshifting. This observation suggests

that DNA replication in B. burgdorferi, like that in M. genitalium, is

accomplished with a restricted set of genes. B. burgdorferi has one

TTGTTTTT

Distribution

(G-C)/(G+C)

0 200 400 600 800 910.725

0.000

0.200

-0.200

Kilobases

Figure 2 Distribution of TTGTTTTT and GC

skew in the B. burgdorferi chromosome. Top,

distribution of the octamer TTGTTTTT. The

lines in the top panel represent the location of

this octamer in the plus strand of the

sequence, and those in the second panel

represent the location of this oligomer in the

minus strand of the sequence. Bottom, GC

skew.

articles

type I topoisomerase (topA) and two type II topoisomerases (gyrase

and topoisomerase IV) for DNA topology management and chro-

mosome segregation, despite its linear chromosomal structure. This

suggests that topoisomerase IV may be required for more than the

separation of circular DNAs during segregation.

The DNA repair mechanisms in B. burgdorferi are similar to those

in M. genitalium. DNA excision repair can presumably occur by a

pathway involving endonuclease III, PolI and DNA ligase. The genes

for two of three DNA mismatch repair enzyme (mutS,mutL) are

present. The apparent absence of mutH is consistent with the lack of

GATC (dam) methylation in strain B31 (S. Casjens, unpublished).

Also present are genes for the repair of ultraviolet-induced DNA

damage (uvrA,uvrB,uvrC and uvrD) (Table 2).

B. burgdorferi has a complete set of genes to perform homologous

recombination, including recA,recBCD,sbcC,sbcD,recG,ruvAB and

recJ. 39-Exonuclease activity associated with sbcB in E. coli may be

encoded by exoA (exodeoxynuclease III). Although recA is present,

we found no evidence for lexA, which encodes the repressor that

BB586

mannose fructose

glucoseglucosamine

F-1-P

M-6-P

M-1-P

Glc-6-P

BB004 BB835

gluconolactone

Gln-6-P

BB152

BB620

glucose-β-R

chitobiose

chitobiose-6-P N-acetyl-Gln-6-P

ribose

BBB04

BBB05

BBB06

glycerol

BB240

N-acetyl-Gln-1-P

BB207

UDP-N-acetyl-Gln

UTP

α 1-4 oligo-glucose, maltose

BB166

EII

BB408

BB629

8 murien synthesis genes

9 cell wall associated genes

BB002 BB151

F-1,6-dP

DHP G-3-P

glycerol-3-P

glycerol

1,3-BPG

3-PG

2-PG

PEP

pyruvate

lactate

BB730

BB020

BB727

BB445

BB241

BB057

BB056

BB658

BB337

BB348

BB087

BB630

BB222

BB636

NADH

NAD+

ATP

ADP

NADH

NAD+

PPi

BB243

BB368

NADH

NAD+

BB055

ATP

ADP

BBB29

BB559

BB645

F-6-P BB407

BB677

BB678

BB679

BB657

BB561

6-P-gluconate ribulose-5-P ribose-5-P

ATP BB544

AMP

NADH

NAD+

acetate

ATP

acetate-P

CoA

BB622

BB589

BB327

BB037

phosphatidic acid

ACP-R

BB704

BB137

BB593

CTP

PPi

CMP-phosphatidic acid

NH2

C-SH

BB362

phosphatidyl glycerol

CMP

G-3-P Pi

acetyl-CoA

fatty acids

ADP

dnaA (BB437), gidA (BB178), gidB (BB177)

Ori initiation

DNA synthesis dnaG (BB710), priA (BB014), dnaB (BB111), RNase H (BB046)

dnaE (BB579), dnaN (BB438), dnaX (BB461), ssb (BB114), ligase (BB552)

DNA topology gyrA,B (BB435/BB436), topA (BB828), parE,C (BB036/BB035)

spoOJ (BB434), helicase (BB607/BB827/BBG34)

Others

recB,C,D (BB634/BB633/BB632), recJ (BB254)

uvrA,B,C,D (BB837/BB836/BB457/BB344)

polI (BB548)

mutS (BB797/BB098), mutL (BB211)

DNA Replication

BB417

BB463

BB618

BB128

BB819

BB571

BB015

rXMP

rIMP

BBB18 BB015

BB463

BB463 BB463

PRPP adenine

BB777

rAMP

PPi

rADP

rATP

rCMP

rCDP

rCTP

rUMP

rUDP

rUTP

rGMP

rGDP

rGTP

BBB17

BB119

BB721

BB575

BB140

BB141

BBI26

drug efflux

BB116

sbcC,D (BB830/BB829), exoIII (BB534)

endonucleases (BB411, BB745)

glycine

serine

BB601

tetrahydrofolate

N5, N10-methylene tetrahydrofolate

N5, N10-methenyl tetrahydrofolate

BB026

ribose

PTS transport

BB558

BB557

BB448

HPr

BB239

BB239 BB791

BB618

BB417

BB128

BB819

BB015BB791

BB793

BB463 BB463 BB463 BB463

dAMP

dADP

dATP

dCMP

dCDP

dCTP

dTMP

dTDP

dTTP

dGMP

dGDP

dGTP

dUMP

dU dCdT

dG dA

BB258

ACP

EII EII

phosphate

glucosamine galactose

N-acetyl-

wall

cell

Protein