## 2 Results
### Transcriptional Regulators and Sensory Histidine Kinases
#### 2.2.5 Cluster E: Regulatory Proteins More Abundant in Pi Limitation than in Pi proficiency in SC
- Regularators with a positive impact on antibiotic biosynthesis and/or morphological differentiation include: - Zur/SCO2508 which, in interaction with Zinc [140], positively controls the expression of the gene encoding the zinc exporter ZitB/SCO6751 [141] and negatively that of the genes encoding an ABC transporter involved in Zn uptake (SCO2505/SCO2506/SCO2507) [141,142], and of a cluster of genes directing the biosynthesis of the zincophore, coelibactin [143]. Consistently, ZitB/SCO6751 was poorly abundant in _SC_ and in _SL_, and to a lesser extent in Pi proficiency (Figure S19 of [9]), whereas proteins of the coelibactin cluster and SCO2506 were more abundant in Pi proficiency than in Pi limitation in _SC_ as in _SL_, to a lesser extent (Figure 10 of [9]). This indicated that Zur is involved in the regulation of _Zn_ homeostasis, maintaining a low intracellular Zn concentration. In _S. avermitilis_, the deletion of _zur_ resulted in decreased production of antibiotics and delayed morphological differentiation [144], as did the addition of Zn in the growth medium of _SC_[145] indicating that Zur plays a positive role in the regulation of antibiotic biosynthesis. * The nickel-responsive regulator SCO4180/Nur that controls the expression of nickel transport and of Fe or Ni-dependent superoxide dismutases [146; 147; 148]. * SCO5464/CabB, a calmodulin-like protein that has a role in calcium homeostasis [149]. * The A-factor dependent regulator AfsR/SCO4426 [150; 151; 152], a global regulator, that has a positive impact on antibiotic biosynthesis [153] and morphological differentiation [154; 155]. * Scr1/SCO4441, which has a strong positive impact on endogenous antibiotic production of _SC_, _SL_, and other _Streptomyces_ strains [156]. * The nucleotide binding protein SCO7699/EshA, which stimulates the accumulation of ppGpp [157; 158]. * The regulator SCO1678, which negatively controls the expression of the divergent operon involved in gluconate metabolism [159]. Regulators with a negative impact on antibiotic biosynthesis and/or morphological differentiation include:  
* The A-factor receptor homolog CprB/SCO6071, which has a negative impact on \(\gamma\)-butyrolactone biosynthesis and thus indirectly on ACT biosynthesis and morphological differentiation [160; 161]. * BldH/SCO2792/AdpA, which activates the transcription of _ramR_, an atypical response regulator that itself activates expression of the genes of the _ramCSAB_ operon required for aerial mycelium formation [162]. * NsdB/SCO7252 [163] and NsdA/SCO5582 [164; 165]. NsdA was more abundant in Pi proficiency than in Pi limitation in _SL_. _nsdA_ is located just upstream of a cluster  
Figure 7: Cluster F, heatmap representation of transcriptional regulators and sensory histidine kinases more abundant in SL than in SC in both Pi conditions. of genes targets of GlnR/SCO4159, an important regulator of N metabolism [166]: _amtB/sco5583_ (ammonium transporter), _glnK/sco5584_ (regulatory protein P-II, cluster I), and _glnD/sco5585_ (protein PII adenylyltransferase) [167]. These proteins were more abundant in Pi proficiency than in Pi limitation in _SL_ as well as in SC but to a far lesser extent (Figure 7 of [9]). Considering the proximity of _ndsA_ with this cluster of genes and its differential abundance in _SL_ and _SC_, NdsA might play a role in the regulation of the expression of genes of this cluster either directly or indirectly via the regulation of _glnR_ expression. Cluster F also includes:  
* The positive regulator of fatty acid biosynthesis, FasR/SCO2366 [168]. FasR was far less abundant in _SC_ than in _SL_, in Pi proficiency, consistent with the previously reported lower phospholipid content of _SC_ compared to _SL_[169]. * SCO5804/NrdR, which represses the expression of class I and class II ribonucleotide reductases encoding genes (RNRs, _nrdAB/sco5225-26_, and _nrd_)/_sco5805_) involved in the conversion of ribonucleotides to deoxyribonucleotides [170,171].