Post on 03-Aug-2018
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Short title: B Vitamin Deficiency and Abiotic Stress 1
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Corresponding author: Andrew D. Hanson, adha@ufl.edu Phone (352) 273-4856 3
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Research Area: Topical Reviews (Associate Editor Julia Bailey-Serres) 5
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Does abiotic stress cause functional B vitamin deficiency in plants? 7 8
Andrew D. Hanson, Guillaume A. Beaudoin, Donald R. McCarty, and Jesse F. Gregory III 9
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Horticultural Sciences Department (A.D.H., G.A.B., D.R.M) and Food Science and Human Nutrition 11
Department (J.F.G.), University of Florida, Gainesville, FL 32611-0690, USA 12
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One-sentence Summary: 15
Unlike animals, plants produce their own B vitamins but may nonetheless suffer vitamin deficiencies 16
under stress conditions, with wide-ranging metabolic consequences. 17
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Author contributions: 20
A.D.H. conceived the article and wrote the manuscript along with G.A.B., D.R.M., and J.F.G. 21
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Funding information: 23
This work was supported by National Science Foundation award IOS-1444202. 24
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Corresponding author: Andrew D. Hanson adha@ufl.edu 26
Plant Physiology Preview. Published on November 2, 2016, as DOI:10.1104/pp.16.01371
Copyright 2016 by the American Society of Plant Biologists
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Abstract 27
B vitamins are the precursors of essential metabolic cofactors, but are prone to destruction under 28
stress conditions. It is therefore a priori reasonable that stressed plants suffer B vitamin deficiencies, 29
and that certain stress symptoms are metabolic knock-on effects of these deficiencies. Given the 30
logic of these arguments, and the existence of data to support them, it is a shock to realize that the 31
roles of B vitamins in plant abiotic stress have had minimal attention in the literature (100-fold less 32
than hormones) and continue to be overlooked. In this article, we therefore aim to explain the 33
connections among B vitamins, enzyme cofactors, and stress conditions in plants. We first outline 34
the chemistry and biochemistry of B vitamins, and explore the concept of vitamin deficiency with the 35
help of information from mammals. We then summarize classical and recent evidence for stress-36
induced vitamin deficiencies and for plant responses that counter these deficiencies. Lastly, we 37
consider potential implications for agriculture. 38 39 Key Words: Biotin, folate, niacin, pantothenate, pyridoxine, riboflavin, thiamin 40
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INTRODUCTION 42
The great pioneers of modern plant physiology pointed out that B vitamins have much in common 43
with hormones, and even classified some vitamins as plant hormones (i.e. plant growth regulators in 44
today’s terms) (Went et al., 1938; Bonner and Bonner, 1948; Thimann, 1963). In plants, as in anim-45
als, B vitamins and hormones are biologically active in minute amounts, are transported, and lead to 46
similarly profound consequences when deficient (Bonner and Bonner, 1948). B vitamins and 47
hormones might consequently be expected to have received comparable research attention. This 48
has broadly been the case in biomedical research since vitamins and hormones were first 49
discovered (Kohler, 1975). It has almost never been the case in any area of plant research, including 50
abiotic stress. Thus, in the Arabidopsis abiotic stress literature, articles involving hormones 51
outnumber those involving B vitamins by a factor of 100 (Supplemental Table S1). 52 53 This stunning disparity suggests two things about past and present thinking in the abiotic stress field. 54
First, it indicates a prevalent default assumption that the whole of B vitamin metabolism always and 55
everywhere continues to work well in stressed plants – and so can be safely ignored. Second, and 56
relatedly, it signals a lack of attention to the possibility that stress-induced defects in B vitamin meta-57
bolism can be intermediate causes of system-wide plant stress responses. Neither the default ass-58
umption nor the inattention is reasonable a priori and they are not justified by the available evidence. 59 60 This review sets out to show that B vitamin deficiency is a simple, probable, but overlooked scenario 61
in abiotic stress responses. We begin by providing key background information on the chemical and 62
metabolic lability of B vitamins and the cofactors derived from them, and on the concept of vitamin 63
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deficiency derived from work in animals. We then revisit classical studies that point clearly to roles 64
for B vitamins in abiotic stress, but are no longer in the modern canon, and assess recent evidence 65
for such roles. Next, we outline how plants combat stress-induced B vitamin deficiencies. Lastly, we 66
consider how understanding stress-induced vitamin deficiency could inform crop breeding and 67
management. 68 69 Two points should be made at the outset. First, there has been much research on the B vitamin con-70
tents of food plants and on B vitamin synthesis and metabolism in plants. However, the main – if not 71
sole – driver for this valuable work has been plants as vitamin sources for humans rather than plants 72
as vitamin sources for themselves (Fitzpatrick et al., 2012; Gerdes et al., 2012). This article takes 73
the complementary position that ‘plants need their vitamins too’ (Smith et al., 2007). Second, re-74
search on vitamin C (ascorbate) shows that plant stress biology does not invariably sideline vitamins 75
(Foyer and Noctor, 2011). This article argues that B vitamins deserve as much attention as vitamin 76
C. 77
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CHEMICAL AND METABOLIC LABILITY – WHY BAD THINGS HAPPEN TO GOOD VITAMINS 79
B vitamins are indispensable because they are the metabolic precursors of essential cofactors. Fig-80
ure 1 shows the seven B vitamins found in plants, along with the cofactors to which they are 81
converted. In brief: Thiamin (vitamin B1) is converted to thiamin diphosphate; riboflavin (vitamin B2) 82
to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD); niacin (vitamin B3) to 83
NAD(P)+; pantothenate (vitamin B5) to coenzyme A and the prosthetic group of acyl carrier protein; 84
pyridoxine (vitamin B6) to pyridoxal 5'-phosphate; biotin (vitamin B8) to the biotinyl side-chain of 85
enzymes; and tetrahydrofolate (historically termed vitamin B9) to various one-carbon substituted 86
folates and their polyglutamylated derivatives. 87 88 Cofactors function by participating in biochemical reactions, e.g. thiamin diphosphate forms covalent 89
complexes with carbonyl substrates, FAD and NAD(P)+ become reduced as substrates are oxidized, 90
and coenzyme A forms thioesters with acyl groups. Cofactors and their vitamin precursors are thus 91
chemically reactive by nature. Their chemically reactive groups are therefore prone to undergo spon-92
taneous side-reactions such as oxidation, hydrolysis, racemization, or addition that damage or des-93
troy the molecule – and stress conditions promote such side-reactions (Piedrafita et al., 2015). For 94
example, most abiotic stresses cause accumulation of reactive oxygen species (You and Chan, 95
2015) that can inflict oxidative damage on every compound in Figure 1. Similarly, temperature extr-96
emes, high light levels, pH excursions, and stress-driven accumulations of metabolites with which 97
cofactors react all directly accelerate diverse types of spontaneous cofactor damage (e.g. Treadwell 98
and Metzler, 1972; Baggott, 2000; Mills et al., 2006; Marbaix et al., 2011). Abiotic stresses can also 99
promote cofactor damage indirectly by altering compartmentation (e.g. Akhtar et al., 2010; Moham-100
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madi et al., 2012), by inducing enzymes that break down cofactors (e.g. Rapala-Kozik et al., 2008; 101
Higa et al., 2012), and by creating harsh cellular conditions in which enzymes that normally act on 102
other substrates become more promiscuous (Piedrafita et al., 2015) and mistakenly attack cofactors. 103 104 Figure 1 uses color-coded arrows to show the site and nature of damage reactions that vitamins and 105
cofactors can undergo in physiological conditions, and Table I catalogs the reactions corresponding 106
to the arrows. Note that Figure 1 is bristling with arrows – which helps explain why most of the B 107
vitamins/cofactors made it into a ‘Top 30’ list of damage-prone metabolites (Lerma-Ortiz et al., 2016) 108
and why all organisms have dedicated systems to deal with vitamin/cofactor damage (Linster et al, 109
2013). “Bad things happen” to B vitamins and cofactors because these compounds are basically 110
chemical and metabolic “accidents waiting to happen”. Also, unlike many other reactive metabolites, 111
cofactors are end-products, not short-lived intermediates that are quickly converted to something 112
else. The longer an end-product lives, the higher the probability of its getting damaged at some point. 113 114 Thiamin diphosphate deserves special mention for metabolic lability because, unlike other cofactors, 115
it can be damaged during the catalytic cycle (‘catalysis-induced inactivation’) (McCourt et al., 2006). 116
Oxygen-dependent side-reactions in enzyme active sites convert the thiamin diphosphate cofactor to 117
an inactive thiazolone derivative (Sümegi and Alkonyi, 1983; Bunik et al., 2007). Such use-depend-118
ent damage explains why thiamin is the only B vitamin whose dietary requirement in animals is pro-119
portional to non-fat energy intake (McCourt et al., 2006). More generally, the damage reactions un-120
dergone by all B vitamins account for their dietary requirements; if vitamins were not continuously 121
damaged they would last forever and not need to be constantly resupplied. In this context it is note-122
worthy that the whole-body half-life of thiamin (and its phosphates) in humans is one to two orders of 123
magnitude shorter than those of other B vitamins for which estimates are available, as follows: thia-124
min, 9.5–18.5 days (Ariaey-Nejad et al., 1970); folates, 60–150 days (Gregory and Quinlivan, 2002); 125
vitamin B6, ~500 days (Coburn, 1990); vitamin B12 (absent from plants), 480–1284 days (Hall, 1964). 126
127
WHAT ACTUALLY CONSTITUTES B VITAMIN DEFICIENCY? 128
The concept of vitamin deficiency comes from human and animal nutrition; it refers to the consequ-129
ences of a shortfall in the dietary supply of a specific vitamin. Because plants make their own B 130
vitamins, and indeed are the ultimate source of most of the B vitamins consumed by animals, the 131
concept of ‘B vitamin deficiency’ might seem inapplicable to plants, and hence irrelevant. But, as we 132
will show, this concept is very relevant to plants. 133 134 Key questions about B vitamin nutrition in animals are: ‘What dietary intake of each vitamin is 135
needed for optimal growth and health?’ and ‘What happens when the supply of a vitamin falls below 136
the optimal level?’ Both questions are often answered by measuring weight gain in young animals 137
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given various vitamin doses in the diet, and by tracking levels of the vitamin and its corresponding 138
cofactor in tissues and organs. Figure 2 (left half) summarizes data from such studies, in which 139
various levels of thiamin, pyridoxine, or folate were supplied to rats whose growth and liver cofactor 140
levels were monitored. Two points that emerge from these data are: (i) There is a continuum rather 141
than a sharp divide between vitamin sufficiency and deficiency; and (ii) the cofactor level in liver 142
does not have to fall much before growth is substantially impacted (as are development, metabolic 143
functions, and behavior, not shown), and declines of 30–60% from optimal are devastating. Animals 144
therefore operate their vitamin and cofactor systems with rather narrow margins of safety. 145 146 The same appears to be true of plants. Nutritional trials analogous to those above have not yet been 147
conducted using totally vitamin-deficient mutants. However, mutant plants partially deficient in thi-148
amin or vitamin B6 have been studied (Woodward et al., 2010; Rueschhoff et al., 2013), as have cult-149
ured cells depleted in folate using a reasonably specific antifolate drug (Loizeau et al., 2008) (Fig. 2, 150
right half). Although these experiments produced a single deficient state, not a range as in rats, the 151
data clearly suggest that a 25–40% loss of cofactor leads to severe consequences. To summarize: 152
The red zone on the B vitamin fuel gauge seems to be in roughly the same place in plants and 153
animals, and is quite close to the full mark. 154 155 A subsidiary concept within vitamin deficiency is ‘functional vitamin deficiency’, wherein vitamin and 156
cofactor measurements need not show marked depletion but strong metabolic disturbances never-157
theless ensue. A prime example is vitamin B12 (absent from plants), whose deficiency in humans is 158
better diagnosed by its metabolic consequences (elevated levels of methylmalonic acid and homo-159
cysteine) than by measuring B12 itself (Stabler et al., 1996). Another example is folate, for which – in 160
contrast to B12 – deficiency causes elevation only of homocysteine and not of methylmalonic acid 161
(Green, 2008). Functional deficiencies of other B vitamins in humans generally affect enzymes hav-162
ing the weakest affinity for their cofactor relative to the cofactor’s intracellular concentration, as is the 163
case for vitamin B6 (Ueland et al., 2015). However, the hierarchy of biochemical reactions most sus-164
ceptible to deficiency of B vitamins has not been fully clarified. 165 166 Functional vitamin deficiencies also can arise when the deficiency occurs in a particular (inaccess-167
ible) tissue or compartment but does not affect the whole organism – or at least the part convenient 168
for assessing vitamin or cofactor status. Such a situation could develop in roots for thiamin and 169
niacin because roots of certain species import these vitamins from shoots (Bonner and Bonner, 170
1948). Intracellular deficiencies are also possible given that B vitamins and cofactors are synthes-171
ized and used in different compartments. For example, thiamin diphosphate is made in the cytosol 172
but used mainly in plastids and mitochondria (Rapala-Kozik et al., 2012), and vitamin B6 is made in 173
the cytosol but used throughout the cell (Fitzpatrick et al., 2011). In this connection, note that the 174
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plastids of the vitamin B6 deficient Arabidopsis mutant in Figure 2 were far more severely deficient in 175
B6 than the leaf as a whole (Rueschhoff et al., 2013), and that a thiamin-requiring tobacco mutant 176
appeared to suffer primarily from thiamin deficiency in chloroplasts (McHale et al., 1988). 177
178
EVIDENCE FOR STRESS-INDUCED B VITAMIN DEFICIENCY 179
The previous sections explained that B vitamins and cofactors are chemically and metabolically un-180
stable, that stresses potentially make them even more unstable, and that modest falls in cofactor 181
levels slow growth. We might therefore predict that (i) abiotic stresses cause vitamin and cofactor 182
deficiencies, (ii) the deficiencies degrade plant performance, and (iii) supplementing stressed plants 183
with the deficient vitamin(s) improves performance. Evidence from both classical and modern work 184
indicates that all these things happen. 185
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Classical Evidence 187
The classical evidence was considered in a short 1957 article with the evocative title ‘The chemical 188
cure of climatic lesions’ (Bonner, 1957). The idea captured in the title was that negative effects of 189
‘climatic lesions’ (i.e. physicochemical environmental stresses) could be ‘cured’ by applying vitamins 190
or other essential metabolites, singly or in mixtures. ‘Chemical cures’ by B vitamins were reported for 191
various plants and various abiotic stresses during the 1940s–1960s; typical data are shown in Figure 192
3. In each case, applying a vitamin or vitamin mixture promoted growth in unfavorable conditions but 193
not in favorable ones. These results are de facto confirmation that stress can lead to functional B 194
vitamin deficiency. Importantly, the Arabidopsis work in Figure 3 gave stress-induced vitamin defic-195
iency a genetic basis by defining ecotypic differences attributable to one or a few genes (Langridge 196
and Griffing, 1959). This is the pattern expected if the enzymes that use a particular cofactor bind to 197
that cofactor with different strengths. When the vitamin starts to run out and cofactor levels fall, the 198
weakest binder loses activity first, and small allelic differences in the affinity of this enzyme for the 199
cofactor become critical determinants of performance of the organism as a whole (Guenther et al., 200
1999). 201
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Modern Evidence 203
Although the exogenous application approach (‘spray and pray’) has fallen out of fashion, it can be 204
perfectly valid, and beneficial effects of applying B vitamins – particularly thiamin – to stressed crop 205
species continue to be reported, e.g. for salinized wheat, sunflower, and maize (Al-Hakimi and 206
Hamada, 2001; Sayed and Gadallah, 2002; Tuna et al., 2013; Kaya et al., 2015). Also, a rigorous 207
Arabidopsis study showed that thiamin enhances tolerance to oxidative stress imposed by paraquat 208
(Tunc-Ozdemir et al., 2009). Such protective effects of thiamin on stressed plants are generally 209
interpreted in terms of the antioxidant properties of thiamin and its diphosphate (Lukienko et al., 210
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2000), but the in-vivo relevance of these properties has been questioned (Lesgards et al. 2015) and 211
it is not clear that the observed protection is due to direct antioxidant effects (Asensi-Fabado and 212
Munné-Bosch, 2010). The experimental data are equally compatible with the protection being due to 213
relief of a functional deficiency of thiamin diphosphate and the consequent restoration of normal 214
metabolic fluxes. Although bias from prior positive reports may be at work, it is interesting that thia-215
min features so prominently in the literature on vitamin application, given that thiamin and thiamin di-216
phosphate are particularly labile in vivo (see above). It is also interesting in the light of the extremely 217
high energetic cost and inefficiency of thiamin biosynthesis (Box 1), to which we will return later. 218 219 Further modern support for stress-induced deficiency of four different B vitamins has come from mol-220
ecular genetics, as follows. (i) Pyridoxine: The Arabidopsis SOS4 (SALT OVERLY SENSITIVE 4) 221
gene for pyridoxal kinase was cloned via the salt-sensitive phenotype of sos4 mutants, which was 222
reverted by pyridoxine (Shi et al., 2002) – a textbook ‘cure’ of a stress lesion. Arabidopsis mutants in 223
the PDX1.3 gene for pyridoxal 5'-phosphate synthase were found to be hypersensitive to salt, 224
osmotic, and oxidative stress (Chen and Xiong, 2005; Titiz et al., 2006). (ii) Pantothenate/coenzyme 225
A: The Arabidopsis HAL3A (HALOTOLERANCE DETERMINANT 3A) gene, first identified for its relat-226
ion to stress tolerance (Espinosa-Ruiz et al., 1999), was shown to code for a key enzyme in panto-227
thenate conversion to coenzyme A (Kupke et al., 2001), and HAL3A overexpression increased salt 228
tolerance (Espinosa-Ruiz et al., 1999; Yonamine et al., 2001). (iii) Folate: Ablation of the Arabidopsis 229
gene encoding a cytosolic folate synthesis enzyme (HPPK/DHPS) specifically impacted salt and 230
oxidative stress-resistance at germination (Storozhenko et al., 2007; Navarrete et al., 2012). (iv) 231
Riboflavin: The Arabidopsis phs1 (PHOTOSENSITIVE 1) mutant, first identified by its sensitivity to 232
high-light stress (Ouyang et al., 2010), was found to lack a functional domain of the riboflavin 233
biosynthesis enzyme PyrR (Hasnain et al., 2013; Frelin et al., 2015). Note the pattern here: Either a 234
gene identified via a stress-sensitive phenotype turned out to be a B vitamin or cofactor synthesis 235
enzyme, or ablating a known B vitamin/cofactor enzyme caused stress sensitivity. 236
237
COUNTERING STRESS-INDUCED B VITAMIN DEFICIENCY 238
Conceptually, resource deficiencies can be countered by (1) maintaining and then mobilizing re-239
serves, (2) obtaining more of the resource, (3) repairing or recycling it, or (4) using less of it. Plants 240
certainly deploy strategies 2 and 3 to confront B vitamin deficiency, and potentially deploy the others. 241 242 Strategy 1: Storing and Mobilizing B Vitamins and Precursors 243
Storage forms of B vitamins have had little attention in the plant literature, in sharp contrast to stor-244
age forms of hormones (Ludwig-Müller, 2011; Piotrowska and Bajguz, 2011). Storage forms of vit-245
amins and vitamin precursors – mainly glucosides and glucose esters – nevertheless exist and some 246
can reach higher concentrations than the corresponding free forms (Gregory, 1998). The only B vita-247
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min for which no storage forms have been reported is thiamin. Storage forms have not been analyz-248
ed in abiotic stress studies, perhaps because they are not commercially available as standards. Un-249
fortunately, this means that the contribution of storage forms to B vitamin homeostasis during stress 250
remains unresolved; this contribution could, however, be large. The main storage forms are shown in 251
Figure 4 and described below, starting with the two vitamins (B6 and B3) whose storage forms are 252
reported to be more abundant than the free forms in certain species and tissues. 253 254 Pyridoxine (B6). The 5'-β-D-glucoside of pyridoxine, and other glycosides linked via the 4- or 5-hydr-255
oxymethyl groups, can contribute up to 75% of the total vitamin B6 in plant tissues (Gregory, 1998), 256
i.e. they can be the largest item in the B6 budget. A glucosyltransferase responsible for pyridoxine-5'-257
β-D-glucoside synthesis has been detected in pea (Tadera et al., 1982); enzymatic hydrolysis of the 258
glucoside has been shown in vitro (Yasumoto et al., 1976) so it can presumably be mobilized in vivo. 259 260 Niacin (B3). Nicotinic acid-N-β-D-glucoside and N-methylnicotinate (trigonelline) are widespread in 261
plants and can be major metabolites of nicotinamide and nicotinate (Matsui et al., 2007; Ashihara et 262
al., 2010); more complex glycosides also occur (Gregory, 1998). Enzymes that would allow the N-263
glucoside and trigonelline to act as mobilizable storage forms have been characterized (Upmeier et 264
al., 1988; Shimizu and Mazzafera, 2000; Mizuno et al., 2014). Brassicaceae contain the β-D-glucosyl 265
ester of nicotinic acid, which almost certainly acts as a mobilizable storage form (Li et al., 2015). 266 267 Pantothenate (B5). Pantothenate 4'-O-β-D-glucoside has been isolated from tomato fruit (Amachi et 268
al., 1971) and is most likely present in a wide range of species and tissues (Yoshizumi and Amachi, 269
1969). Glycosides of the lactone form of pantoate, the immediate precursor of pantothenate (pant-270
oyllactone-β-D-glucopyranoside and pantoyllactone primeveroside) occur in rice seedlings, the lev-271
els in coleoptile tissue being in the millimolar range (Menegus et al., 2002). These pantoate derivat-272
ives seem not to have been sought in any plant besides rice; they could conceivably be widespread. 273 274 Tetrahydrofolate Precursors. The precursor p-aminobenzoate was converted to its β-D-glucosyl 275
ester by all tissues and species tested and was found to be the major endogenous form of p-amino-276
benzoate (Quinlivan et al., 2003). The esterification reaction is reversible and the ester is stored in 277
vacuoles (Eudes et al., 2008). Glycosides (probably β-D-glucosides) of the tetrahydrofolate precurs-278
ors neopterin and monapterin were found in tomato fruit engineered to overproduce pterins (Díaz de 279
la Garza et al., 2004); it is not known whether such glycosides occur naturally, or whether they can 280
be mobilized. 281 282 Riboflavin (B2). The α and β forms of riboflavin-5′-D-glucoside have been found in germinating barl-283
ey seedlings supplied with riboflavin (Suzuki and Uchida, 1983). As with the pterin glycosides above, 284
it is it is not known whether riboflavin glucosides occur naturally, or whether they can be mobilized. 285 286
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Biotin (B7). While no small-molecule conjugates of biotin have been reported, a biotinyl protein that 287
represents >90% of the total protein-bound biotin has been characterized and cloned from pea 288
seeds (Dehaye et al., 1997), and is conserved among higher plants (Gerdes et al., 2012). 289 290 Strategy 2: Increasing B Vitamin Supply 291
Many analyses of gene and protein expression have indicated that abiotic stresses upregulate flux 292
through some but not all B vitamin biosynthesis pathways and studies of the effects of stress on the 293
levels of vitamins and cofactors tend to support this inference. As is usual in stress research, 294
differences in experimental design (the species and tissue used, the timing, duration, and severity of 295
stress, the analysis methods applied – blots/microarrays/RNAseq, etc) preclude meta-analysis of all 296
the data. Below, we therefore focus first on a high-throughput dataset – the AtGenExpress global 297
stress expression dataset (available at http://jsp.weigelworld.org/expviz/expviz.jsp) – supplemented 298
with broadly comparable data from several independent Arabidopsis stress studies (Supplemental 299
Table S2). We then highlight illustrative papers on pyridoxine and thiamin. 300 301 Note that even when a vitamin biosynthetic pathway is clearly upregulated in response to stress, 302
stress-induced vitamin or cofactor deficiency may still occur for several reasons. Firstly, activating 303
biosynthetic gene expression may fail to increase vitamin production due to downstream constraints, 304
e.g. the energy cost of making THI4 protein for thiamin biosynthesis (see below and Box 1). Sec-305
ondly, as noted above, a high vitamin or cofactor status – as measured in whole organs, tissues, or 306
cells – can obscure functional deficiencies within sub-compartments. Lastly, conversion of vitamins 307
to cofactors may become limiting, so that increases in vitamin levels do not always result in higher 308
cofactor levels. Cofactor levels can consequently fall even when free vitamin levels rise – and cofact-309
or levels – not vitamin levels – determine metabolic outcomes. 310 311 Arabidopsis Gene Expression. The stresses used for the AtGenExpress global stress expression 312
dataset (heat, cold, drought, salt, high osmolarity, UV-B light, and wounding) were essentially single-313
regime shock treatments, lasting 24 hours or less, given to Arabidopsis seedlings (Kilian et al., 314
2007); the protocols in the other studies listed in Supplemental Table S2 were quite similar. The 315
transcriptional responses observed in these experiments therefore necessarily only included part of 316
the plant’s full repertoire. These responses nonetheless follow the coherent pattern seen in Figure 5, 317
a bird’s-eye schematic of B vitamin synthesis and salvage pathways in which enzymes are 318
represented by rectangles. The color density of each enzyme is proportional to the number of differ-319
ent stresses that induce the corresponding gene by two-fold or more. The pathways are arranged in 320
order of prevalence of gene induction. At one extreme (biotin, pantothenate/CoA, and tetrahydro-321
folate pathways) just one or two biosynthetic genes are induced by a single stress, whereas at the 322
other extreme (vitamin B6 and thiamin pathways) all the known biosynthetic genes are induced by at 323
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least three stresses. Except for B6, the prevalence of induction of salvage genes basically tracks that 324
of biosynthetic genes. This overview of gene-level data thus indicates that certain B vitamin biosyn-325
thesis pathways – particularly those for B6 and thiamin – are upregulated by several abiotic stresses 326
and that others – such as the tetrahydrofolate pathway – are largely not. Vitamin/cofactor analysis 327
data and protein-level data for vitamin B6 and thiamin are consistent with this picture, as discussed 328
next. 329 330 Vitamin B6. Pyridoxal 5′-phosphate is made by the pyridoxal synthase complex, which consists of 331
two proteins, PDX1 and PDX2 (the two red-colored boxes in the pyridoxal 5′-phosphate section of 332
Figure 5). Arabidopsis has three PDX1 homologs, of which PDX1.1 and PDX1.3 are active enzymes 333
and PDX1.2 is a positive regulator (Titiz et al., 2006; Moccand et al., 2014). Paralleling the stress 334
induction of Arabidopsis PDX genes (Fig. 5; Supplemental Table S2), PDX1.3 protein accumulated 335
and the total B6 level increased by 60% in response to UV-B exposure (Ristilä et al., 2011); total B6 336
also increased by 60% in response to heat stress (Moccand et al., 2014). Levels of pyridoxal 5'-337
phosphate and free pyridoxal or pyridoxine likewise increased by about two-fold in tobacco exposed 338
to chilling, UV radiation, osmotic stress, oxidative stress, or drought (Huang et al., 2013). 339 340 Thiamin. Thiamin is synthesized by a pathway that is very energetically expensive because the thi-341
azole moiety is made by a suicide enzyme (THI4), and the pyrimidine moiety is made by a radical 342
SAM (S-adenosylmethionine) enzyme (THIC) that probably lasts for only a few catalytic cycles (Box 343
1). Paralleling the stress induction of Arabidopsis THI4, THIC, and other thiamin synthesis genes 344
(Fig. 5; Supplemental Table S2), the level of total thiamin and of its components (thiamin mono- and 345
diphosphates and free thiamin) increased by up to two-fold in Arabidopsis seedlings subjected to 346
cold, osmotic, salinity, or oxidative stress (Tunc-Ozdemir et al., 2009). Similarly, total thiamin 347
increased by up to 60% in Arabidopsis seedlings exposed to salt, osmotic, or oxidative stress, with 348
free thiamin contributing as much or more than thiamin diphosphate to the increase (Rapala-Kozik et 349
al., 2012). Also similarly, in maize seedlings subjected to water, salt, or oxidative stress, total thiamin 350
increased by 70-150%, due to increases in free thiamin and thiamin monophosphate (Rapala-Kozik 351
et al., 2008). However, in this case levels of the cofactor thiamin diphosphate stayed constant or fell 352
by up to 30%, which is quite enough to cause severe deficiency symptoms (Fig. 2) and illustrates the 353
point made above about cofactor levels falling even though free vitamin levels rise. 354 355 Given the suicide nature of the THI4 enzyme, it is striking that THI4 was the most highly or second 356
most highly induced gene in cotton seedlings exposed to cold, drought, salt, or high pH stress; the 357
induction of THI4 relative to unstressed controls ranged from 14-fold to 44-fold (Zhu et al., 2013). It 358
is equally striking that the THI4 protein showed, among all proteins analyzed, the second largest 359
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increase in expression (3.2-fold) in heat-stressed poplar leaves (Ferreira et al., 2006) and the third 360
largest increase in expression (3.7-fold) in heat-stressed wild rice leaves (Scafaro et al., 2010). 361 362 Strategy 3: Repairing or Recycling Damaged B Vitamins and Cofactors 363
Like other organisms, plants have enzyme systems that deal with some of the chemical and enzym-364
atic damage reactions shown in Figure 1 (Linster et al., 2013). These enzyme systems may repair 365
damaged vitamins and cofactors, i.e. directly restore them to the original state, or salvage parts of 366
damaged molecules for re-use in biosynthesis. As vitamin and cofactor repair (Hanson et al., 2016) 367
and recycling (Gerdes et al., 2012) were recently reviewed, we focus here on three cases where the 368
repair or recycling-related activity appears to be upregulated by stress and not simply constitutive. 369 370 Thiamin Salvage Hydrolase TenA_E. TenA_E mediates two successive steps in the recovery of 371
the pyrimidine moiety from thiamin damaged in the thiazole moiety (Zallot et al., 2014). The Ara-372
bidopsis gene encoding TenA_E is upregulated by several abiotic stresses, in common with thiamin 373
synthesis genes (Fig. 4; Supplemental Table S2). The Arabidopsis gene specifying the thiazole 374
salvage enzyme ThiM (Yazdani et al., 2013) is not upregulated (Fig. 4), which fits with the thiazole 375
moiety of thiamin being more prone to irreversible damage than the pyrimidine moiety, and hence 376
not as recyclable (Zallot et al., 2014). 377 378 Thiamin Diphosphate-related Nudix Hydrolases. These enzymes (NUDT20 and NUDT24 in Ara-379
bidopsis) are diphosphatases whose preferred substrates are damaged – and toxic – forms of thiam-380
in diphosphate, including the previously mentioned thiazolone form generated by oxygen-dependent 381
side-reactions (Goyer et al., 2013). The diphosphatase reaction is both a detoxification step and the 382
first step in salvage of the pyrimidine moiety. The Arabidopsis gene(s) (which are not distinguished 383
by microarrays) are induced between two-fold and five-fold by salt, drought, and osmotic stress, and 384
probably also oxidative stress (Kilian et al., 2007; Goyer et al., 2013). 385 386 NAD(P)+ Salvage Module. Two enzymes mediating consecutive steps in NAD(P)+ salvage (nicotin-387
amidase and nicotinate phosphoribosyltransferase) are each induced by two stresses in Arabidopsis 388
(Fig. 5), as is a transporter (NiaP) for nicotinate, the intermediate that these enzymes share (Kilian et 389
al., 2007). Arabidopsis NiaP also transports trigonelline (Fig. 4) (Jeanguenin et al., 2012). NiaP is 390
probably located in the plasma membrane (Jeanguenin et al., 2012), suggesting that nicotinate salv-391
aged in one location could be re-used for NAD(P)+ synthesis in another. This would be consistent 392
with the classical evidence for inter-organ exchange of nicotinate (Bonner and Bonner, 1948). 393
394
Strategy 4: Decreasing Demand for B Vitamins 395
Metabolism can sometimes be re-routed to bypass certain cofactor-dependent steps, as in the phos-396
phate starvation response, in which alternative bypass pathways of cytosolic glycolysis are upregul-397
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12
ated to spare scarce adenylates and phosphate (Plaxton and Tran, 2011). There are as yet no cases 398
of full-blown re-routing in response to vitamin deficiency, although two studies provide indirect evi-399
dence for redirection of fluxes that may be, at least in part, active responses. In the first study, 400
tobacco leaves overexpressing transketolase, a thiamin diphosphate-dependent enzyme, became 401
moderately thiamin diphosphate-deficient, and showed reduced isoprenoid synthesis via the thiamin 402
diphosphate-dependent enzyme 1-deoxy-D-xylulose 5-phosphate synthase (DXS); this reduction 403
was associated with lower DXS transcript levels (Khozaei et al., 2015). In the second study, a 404
drastic, rapid-onset tetrahydrofolate deficiency in Arabidopsis cells treated with antifolate drugs led 405
to initial depletion of methionine and S-adenosylmethionine pools, reflecting reduction in the tetra-406
hydrofolate-dependent flux of one-carbon units to methionine as one-carbon fluxes were adaptively 407
reprioritized in favor of nucleotides (Loizeau et al., 2007). Surprisingly, the methionine and S-aden-408
osylmethionine pools – and by inference the associated fluxes – subsequently returned to normal, in 409
part via a conserved adaptive mechanism, triggered by tetrahydrofolate deficiency, that involves 410
proteolytic removal of the N-terminal regulatory region of the methionine synthesis enzyme 411
cystathionine γ-synthase (Loizeau et al., 2007). 412
413
AGRICULTURAL IMPLICATIONS 414
As Abraham Blum has emphasized (Blum, 2014), humility and caution are needed when trying to 415
predict agricultural benefits by extrapolating from the responses of seedlings of Arabidopsis or other 416
species to short, sharp stresses in growth chambers (which describes most of the experiments cov-417
ered above). With this warning in mind, what might stress-induced B vitamin and cofactor deficiency 418
imply for crop breeding and management? The primary implication is that breeding for enhanced vit-419
amin content (biofortification) – by transgenic or other approaches – could pay off in terms of stress-420
resistance as well as human nutrition (Fitzpatrick et al., 2012). If stress indeed predisposes to defic-421
iency, a clear prescription for stress-resistance breeding would be: ‘Keep your cofactors safe’. 422 423 The two B vitamins most connected with stress responses, vitamin B6 and thiamin (Fig. 5), are 424
targets of transgenic biofortification efforts in Arabidopsis (Raschke et al., 2011; Pourcel et al., 2013; 425
Vanderschuren et al., 2013; Dong et al., 2015), and stress tests have been run on the engineered 426
plants, albeit mainly with plantlets cultured on agar medium containing sucrose (i.e. not photo-427
synthesizing normally). The total B6 content of leaf tissue was boosted up to four-fold, and included 428
large increases in the cofactor pyridoxal 5'-phosphate and pyridoxine-5'-β-D-glucoside (Raschke et 429
al., 2011). The total thiamin content of leaf tissue was boosted up to 3.4-fold, contributed by up to 430
two-fold increases in the cofactor thiamin diphosphate and up to six-fold increases in thiamin (Dong 431
et al., 2015). The B6-biofortified plants were larger than controls and more resistant to paraquat-432
imposed oxidative stress; no other stress data were reported (Raschke et al., 2011). The thiamin-433
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13
fortified plants showed no change in resistance to salt, cold, osmotic, drought, or oxidative stress 434
(Dong et al., 2015). To summarize: These first biofortification results for B6 and thiamin are incon-435
clusive and merit follow-up. 436 437 Stress-induced B vitamin deficiency also has implications for crop management (Plaut et al., 2013). 438
Reported benefits of vitamin applications are cited above; such applications are most likely to be 439
useful in practice if they can be given as seed-priming treatments (Al-Hakimi and Hamada, 2001), 440
i.e. applied to seed before sowing. Such seed treatments are cost-efficient (Tanou et al., 2012). 441
442
FUTURE PERSPECTIVES 443
The preceding overview of work relating B vitamins to abiotic stress raises five issues that are listed 444
in the Outstanding Questions Box. Each issue is developed briefly below 445 446 Itemizing Stress-relevant Enzyme Reactions. Although various enzymes and genes for repair or 447
recycling of damaged vitamins and cofactors are known, this is still not the case for about half of the 448
30 damage reactions in Figure 1. While the products of some of these reactions may have no 449
possible fate besides complete degradation, comparative biochemistry suggests that others may 450
well be reclaimed in plants; examples include biotin sulfoxide and chain-shortened biotin (Linster et 451
al., 2013), pyridoxine and nicotinamide N-oxides (Sakuragi and Kummerow, 1960; Shibata et al., 452
1991), and riboflavin-4',5'-phosphate (cyclic FMN) (Fraiz et al., 1998). Nor do we know most of the 453
enzymes or genes for the synthesis and mobilization of the vitamin conjugates in Figure 4, and it is 454
not even clear that we have fully inventoried the conjugates that plants can make. Notably, conjug-455
ated forms of thiamin and its pyrimidine and thiazole precursors have not been reported from plants, 456
but they seem not to have been sought. 457 458 Graduating to Crops and Realistic Stress. As noted previously, most of the modern data linking 459
abiotic stress with B vitamins and cofactors comes from young Arabidopsis plants and unrealistic 460
stress protocols. This is a generic weakness of molecular-level stress research, and the resulting 461
disconnect from agriculture goes a long way toward explaining why molecular work has had a very 462
limited impact on breeding for stress environments (Blum, 2014). It is consequently important to 463
extend stress/vitamin work from Arabidopsis to good genetic model crops such as tomato, canola, 464
maize, and rice, and to adopt stress protocols that mimic field stresses to plants beyond the seedling 465
stage. 466 467 Diagnosing Functional Deficiencies. Vitamin deficiencies, particularly functional ones affecting on-468
ly certain cells or compartments, may be better diagnosed from characteristic changes in metabolite 469
profiles than by directly measuring vitamin levels, as discussed above for vitamin B12 deficiency in 470
humans (Stabler et al., 1996). Given the possibility that direct vitamin measurements can fail to 471
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14
detect subtle but physiologically critical functional deficiencies, and the high cost and low-throughput 472
nature of many vitamin assays, indirect assessment of plant vitamin and cofactor status via metabol-473
omics is appealing. Confirming or disconfirming the validity of this approach in plants, as in humans 474
(Stabler et al., 2013), will require prior metabolic profiling studies of vitamin-deficient mutants. An 475
alternative indirect, high-throughput way to detect functional vitamin deficiencies may be via charact-476
eristic transcriptome changes, analogous to the induction of specific genes by mineral nutrient defic-477
iencies (e.g. Nikiforova et al., 2003; Zheng et al., 2009). Furthermore, transcriptome analysis could 478
uncover mechanisms that re-route metabolism to mitigate the effects of vitamin deficiency (see 479
above). Again, evaluation of these possibilities will require studies of vitamin-deficient mutants. 480
481
Genotypic Variation. Although there is natural genotypic variation in vitamin content (Hanson and 482
Gregory, 2011; Fitzpatrick et al., 2012), it would be impractical to use vitamin content as a selection 483
criterion to develop experimental populations due to the issues of assay cost and efficacy just outlin-484
ed. On the other hand, were high-throughput indirect methods to assess deficiency available (see 485
above), it would be feasible to assess vitamin/cofactor status in populations subjected to realistic 486
stresses, and then to work back via genome-wide association studies to genes governing 487
vitamin/cofactor status. Once identified, such genes, which would presumably include known and 488
novel genes with repair/recycling, synthesis, storage, or bypass functions, could be used to explore 489
a ‘keep your cofactors safe’ breeding strategy for abiotic stress resistance. 490 491 Is Thiamin an Achilles’ Heel in Stress Metabolism? A thread running through the whole of this re-492
view is that thiamin and thiamin diphosphate are not like the other B vitamins and cofactors. Thiamin 493
diphosphate may turn over exceptionally fast, at least in part because of its unusual feature of 494
catalytic inactivation. Thiamin is energetically costly to make due to the suicidal nature of one of its 495
biosynthetic enzymes and the suicidal tendency of another. Because thiamin synthesis depends 496
absolutely on concurrent protein synthesis it is vulnerable to stress in a way that other B vitamins are 497
not. Unlike most other B vitamins, thiamin and its precursors lack known storage forms. Thiamin 498
synthesis and salvage genes are particularly highly stress-regulated in Arabidopsis seedlings. And 499
lastly, thiamin is more prominent than other B vitamins in the ‘spray and pray’ literature. Taken 500
together, these features suggest that thiamin could be an Achilles’ heel – a crucial weak point – in 501
plant stress metabolism. 502
503
Supplemental Data 504
The following supplemental materials are available. 505
• Supplemental Table S1. Analysis of Arabidopsis stress literature based on PubMed search 506
terms. 507
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15
• Supplemental Table S2. Stress-induced B vitamin/cofactor synthesis and salvage genes in 508
Arabidopsis. 509
510
ACKNOWLEDGMENTS 511
We apologize to the authors of relevant studies that could not be cited here due to page limitations, 512
and thank Dr. Claudia Lerma Ortiz for a helpful critique of a draft of the review. 513
514
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16
515
Box 1. Thiamin Biosynthesis – A High-cost, High-risk Operation 516
Enzymes all have finite lifespans, but some have much shorter lifespans than others. These include 517
so-called ‘suicide enzymes’ in which a residue is irreversibly altered after just one turnover, as well 518
as enzymes employing reactive radicals as intermediates, e.g. radical S-adenosylmethionine (SAM) 519
enzymes, which typically catalyze fewer than a dozen turnovers in vitro (Broderick et al., 2014). 520
Enzymes with short lifespans are energetically costly because they have to be replaced so often. 521 522 Thiamin is much more energetically costly to produce than other vitamins because its first biosynth-523
etic enzymes, THI4 and THIC, have extremely short lifespans. THI4 (also called THI1) synthesizes 524
the thiazole moiety of thiamin (Figure). The sulfur atom in the thiazole ring comes from a conserved 525
cysteine in THI4 whose loss permanently inactivates the protein, making THI4 a suicide enzyme 526
(Chatterjee et al., 2013). THIC synthesizes the pyrimidine moiety of thiamin. THIC is a radical SAM 527
enzyme that may achieve no more than five catalytic turnovers in vitro (Palmer and Downs, 2013). 528
Thus THI4 and THIC mediate orders of magnitude fewer catalytic events during their lives than most 529
other enzymes. 530 531 This catalytic inefficiency is manifested in vivo. In proteomic analyses of barley leaves, the THI4 and 532
THIC proteins had, respectively, the first and fifth highest turnover rates of more than 500 proteins 533
studied (Nelson et al., 2014). The half-lives of THI4 and THIC were just a few hours compared to 534
days for most proteins. 535 536 Another consequence may be high vulnerability of the thiamin biosynthetic pathway to stress. Global 537
responses to abiotic stress include shutting down protein synthesis in general (Dhindsa and Cleland, 538
1975; Good and Zaplachinski, 1994) and specifically inducing proteins involved in protein folding and 539
processing (Liu and Howell, 2010). Such reprioritization could adversely impact the replacement of 540
THI4 and THIC, without which thiamin synthesis cannot proceed. 541
542
Box 1 Figure. Catalytic longevity and protein turnover in thiamin synthesis. The number of catalytic 543
turnovers that each pathway enzyme mediates during its lifetime (represented by the width of the 544
blue reaction arrows) varies from thousands to <10 for THIC and one for THI4. The consequent 545
rapid turnover of the THIC and THI4 proteins is schematized by red arrows. Abbreviations: AIR, 546
aminoimidazole ribotide; HET, hydroxyethylthiazole, HMP, hydroxymethylpyrimidine, P, phosphate, 547
PP, diphosphate. 548
549
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17
550
Advances Box 551
● Recent research and the classical literature on ‘the chemical cure of climatic lesions’ converge to 552
indicate that stressed plants can develop functional B vitamin deficiencies. 553
● Fully appreciating the lability and metabolic centrality of B vitamins and cofactors makes clear that 554
they are crucial stress-sensitive nodes in pathway networks that cells must seek to protect. 555
● Protection strategies include repairing or recycling damaged vitamins and cofactors, increasing 556
biosynthesis by upregulating biosynthetic gene expression, and probably mobilizing reserves. 557
● Thiamin is the most metabolically labile B vitamin and the only one whose synthesis depends on 558
suicidal enzymes, implying that thiamin pools are doubly difficult to maintain in stress conditions. 559
560
561
Outstanding Questions Box 562
● Have we documented all the relevant metabolic reactions of B vitamins and cofactors? 563
● Do the results from model stresses in Arabidopsis apply to realistic stresses in crops? 564
● Can functional B vitamin deficiency be diagnosed from metabolome/transcriptome changes? 565
● How far can genotypic variation in vitamins or cofactors explain variation in stress resistance? 566
● Is thiamin really the most stress-sensitive B vitamin? 567
568
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18
FIGURE LEGENDS 569
570
Figure 1. Structures and damage reactions of the seven B vitamins found in plants and of repres-571
entative cofactors derived from them. The vitamin moieties are highlighted in blue. Note that folates 572
generally have a short γ-linked polyglutamate chain attached to the glutamyl moiety. Color-coded 573
arrows show the site and nature of spontaneous chemical or enzymatic damage reactions that each 574
vitamin/cofactor can undergo in vivo. The damage reactions involved are documented in Table I. 575
576
Figure 2. Comparing growth responses to deficiencies of thiamin, B6, or folate in rats versus plants. 577
The decline from vitamin sufficiency to deficiency is approximated by a color gradient. For rats, 578
deficiencies were obtained by varying dietary vitamin content; liver was used to assess vitamin 579
status. For plants, the experiments involved vitamin deficient mutants (blk-1 for thiamin in maize, 580
pdx1.3 for B6 in Arabidopsis) or cell cultures treated with an antifolate drug for folate in Arabidopsis. 581
Whole plants, leaves, or cells were used to assess vitamin status. Data sources: rat thiamin, Rains 582
et al. (1997); rat B6, Mackey et al. (2003) and Scheer et al. (2005); rat folate, Clifford et al. (1993); 583
maize thiamin, Woodward et al. (2010); Arabidopsis B6, Rueschhoff et al. (2013); Arabidopsis folate, 584
Loizeau et al. (2008). 585
586
Figure 3. Classical data on the chemical cure of high- or low-temperature growth lesions. Day/night 587
temperatures are in ºC. +, Vitamin(s) added; – , no vitamin; differences significant at * P <0.05, ** P 588
<0.01. The data are for species of the ornamental plant Cosmos (Bonner, 1943), for Arabidopsis 589
(Langridge and Griffing, 1959), and for other species (Ketellapper, 1963). 590
591
Figure 4. Structures of conjugated forms of B vitamins and their precursors that occur in plants. The 592
molecules to which the vitamins and precursors are conjugated are colored blue. 593
594
Figure 5. Stress induction of B vitamin and cofactor synthesis and salvage genes in Arabidopsis. 595
Synthesis and salvage pathways for each vitamin are schematized as in Gerdes et al. (2012) except 596
for the omission of compartmentation and the addition of two thiamin salvage reactions (Yazdani et 597
al., 2013; Zallot et al., 2014). Circles are metabolites, arrows are reactions, and rectangles are 598
enzymes. The full pathway schemes, which include enzyme and metabolite names, are available at 599
http://pubseed.theseed.org/seedviewer.cgi?page=PlantGateway. Enzymes whose genes are induc-600
ed at least two-fold by 0, 1, 2, or ≥3 different abiotic stresses (in shoots or roots) are color coded 601
white and three shades of red, respectively. Gene expression data were taken from AtGenExpress 602
and literature summarized in Supplemental Table S2. 603
604
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19
Table I. Chemical and enzymatic damage reactions of B vitamins and the corresponding cofactors
Vitamin/cofactor Reactions C/Ea Referencesb
Thiamin (vitamin B1) Thiamin diphosphate
Pyrimidine ring deamination Thiazole ring oxidation Thiazole ring breakdown Oxidation to thiamin acetate Hydrolysis to thiazole + pyrimidine Dephosphorylation Thiamin triphosphate formation
C C,E C E E E E
Windheuser and Higuchi, 1962 Bunik et al., 2007; Dwivedi and Arnold, 1973 Jenkins et al., 2007 Dalvi et al., 1974 Jurgenson et al., 2009 Rapala-Kozik et al., 2009 Linster et al., 2013
Riboflavin (vitamin B2) FMN, FAD
(Photo)oxidative flavin ring loss (Di)phosphate bond hydrolysis 7α- and 8α-hydroxylation Cyclic FMN formation from FAD
C E E
C,E
Choe et al., 2005 Ogawa et al., 2008; Rawat et al., 2011 Ohkawa et al., 1983 Pinto et al., 1999; Sánchez-Moreno et al. 2009
Niacin (vitamin B3) NAD(P)(H)
Hydration of nicotinamide ring Epimerization of β- to α-NAD(P)H Hydrolytic loss of nicotinamide ring Diphosphate bond hydrolysis Nicotinamide ring addition reactions
C,E C E E C
Marbaix et al., 2011 Oppenheimer and Kaplan, 1975 Everse et al., 1975 Ogawa et al., 2008 Everse et al., 1971
Pantothenate (vitamin B5) Coenzyme A, ACPc
Oxidations of the thiol group Diphosphate bond hydrolysis Hydrolysis of the 3' phosphate group
C E E
Huang et al., 2016 Ogawa et al., 2008 Paizs et al., 2008
Pyridoxine (vitamin B6) Pyridoxal 5'-phosphate
Aldehyde group oxidation Aldehyde group condensations Dephosphorylation 6-Hydroxylation
C/E C E C
Gerdes et al., 2012 Dalling et al., 1976 Gerdes et al., 2012 Tadera et al., 1986
Biotin (vitamin B8) Biotinylated enzymes
Oxidation to biotin sulfoxide Side chain β-oxidation
C E
Melville, 1954 Izumi et al., 1973
Tetrahydrofolate C1-Substituted folates
Oxidative cleavage of C9-N10 bond Pteridine ring oxidation 5-Formyltetrahydrofolate formation γ-Glutamyl bond hydrolysis
C C/E C/E E
Gregory, 1989 Noiriel et al., 2007 Baggott, 2000; Goyer et al., 2005 Orsomando et al., 2005; Bozzo et al., 2008
605 aC, chemical (i.e. non-enzymatic, spontaneous) reaction; E, enzymatic reaction or side-reaction. 606 bCertain reactions have so far been reported only from animals or microbes. cACP, acyl carrier protein, which has a bound 4'-phosphopantetheinyl prosthetic group derived from coenzyme A.
607
608
609
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