Small-molecule inhibition of pyruvate phosphate dikinase targeting the nucleotide binding site

Pyruvate phosphate dikinase (PPDK) is an essential enzyme of C4 photosynthesis in plants, catalyzing the ATP-driven conversion of pyruvate to phosphoenolpyruvate (PEP). It is further used by some bacteria and unicellular protists in the reverse, ATP-forming direction. Many weed species use C4 photosynthesis in contrast to world's major crops, which are C3 plants. Hence inhibitors of PPDK may be used as C4-specific herbicides. By screening a library of 80 commercially available kinase inhibitors, we identified compounds derived from bisindolylmaleimide (bisindolylmaleimide IV, IC50 = 0.76 ± 0.13 μM) and indirubin (indirubin-3'-monoxime, IC50 = 4.2 ± 0.9 μM) that showed high inhibitory potency towards PPDK and are among the most effective PPDK inhibitors described today. Physiological studies on leaf tissues of a C4 model plant confirmed in vivo inhibition of C4-driven photosynthesis by these substances. Moreover, comparative docking studies of non-inhibitory bisindolylmaleimide derivatives suggest that the selectivity towards PPDK may be increased by addition of functional groups to the core structure

Lifestyle: Substance Use—Nicotine, Alcohol and Drugs

Use of substances including alcohol, tobacco and drugs is common in people of reproductive age, can lead to dependence and is a major global health concern. Despite targeted public health policies and campaigns, population surveys (National Institute on Drug Abuse (NIH) 2020; European Drug Report 2019) continue to highlight widespread use of substances, often in combination, which have substantial negative implications for health in general and the potential to harm future generations (Stephenson et al. 2018). Healthcare professionals need to be aware of the complex psychological, physiological and social factors that may be linked to substance use and be prepared to offer counselling and referral for specialist services. Pregnancy, however, can be a ‘window of opportunity’ and a motivating factor for women and their partners to change their behaviour and minimise risk with help to quit or cut down on substance use (Solomon and Quinn 2004). Preconception care offers the opportunity to further reduce risk by helping to modify consumption prior to pregnancy