Discover how the carboxyspermidine dehydrogenase enzyme in gut bacteria produces spermidine, a compound with remarkable health benefits
Polyamines are positively charged alkylamines containing multiple amine groups that are essential to nearly all forms of life, from humans to bacteria and archaea. These small organic compounds might not be household names, but they play crucial roles in numerous biological processes 1 2 .
Did you know? The most prevalent polyamines include the diamine putrescine and the triamine spermidine. While humans can produce polyamines through metabolic processes and obtain them from dietary sources, a significant portion comes from an unexpected source: the metabolic activities of our gut microbiome 1 2 .
The spermidine in your body comes from three primary sources: dietary intake, your own metabolic production, and uptake of polyamines manufactured by your gut microbes 1 2 . What's fascinating is that humans and most eukaryotes use a different biosynthetic pathway than many gut microbes:
In 2023, a team of researchers conducted groundbreaking research to characterize CASDH from Bacteroides fragilis (BfCASDH), providing the first detailed look at this crucial microbial enzyme 1 6 .
Researchers identified the genes encoding CASDH in Bacteroides fragilis and Clostridium leptum
The team heterologously expressed CASDH genes in E. coli BL21 cells
Using nickel-chelating sepharose affinity chromatography
Using steady-state kinetic methods with various substrates
The experimental results yielded several important discoveries:
Kinetic analysis demonstrated that BfCASDH strongly prefers NADPH over NADH as its coenzyme, with NADH initial rates barely detectable 1 .
Evidence of cooperativity between the two active sites of dimeric BfCASDH was found—a sophisticated form of molecular regulation 1 .
| Substrate | kcat (s⁻¹) | Km (mM) | kcat/Km (M⁻¹s⁻¹) | Hill Coefficient |
|---|---|---|---|---|
| Putrescine | 0.41 ± 0.02 | 4.2 ± 0.3 | 96 ± 7 | 2.1 ± 0.2 |
| DAP | 0.34 ± 0.03 | 19.7 ± 3.6 | 17 ± 3 | 1.8 ± 0.1 |
| ASA | 0.64 ± 0.02 | 2.7 ± 0.1 | 230 ± 15 | 1.5 ± 0.1 |
| NADPH | 0.39 ± 0.05 | 0.057 ± 0.003 | 6700 ± 200 | - |
The significance of alternative spermidine biosynthesis pathways extends far beyond human gut microbes. Recent research has discovered an even more unusual CAPA pathway in cyanobacteria (Synechocystis sp. PCC 6803) that produces spermidine without using putrescine as an intermediate 5 .
The characterization of CASDH represents more than just academic interest—it opens doors to potential therapeutic applications. The dysregulation of spermidine production in the gut has been associated with tumor progression in pancreatic and colorectal cancers 1 . Conversely, spermidine supplementation has been shown to protect mice from colorectal carcinogenesis 1 .
Dysregulated spermidine production linked to tumor progression in pancreatic and colorectal cancers 1
Spermidine supplementation shown to protect mice from colorectal carcinogenesis 1
The unique structure and mechanism of microbial CASDH enzymes also make them potential targets for antimicrobial strategies that could selectively disrupt polyamine biosynthesis in pathogens without affecting human metabolic pathways. As we continue to unravel the complex metabolic partnerships between humans and their microbial inhabitants, each discovery brings us closer to harnessing this knowledge for better health outcomes.
The humble gut bacterium, once overlooked, is now recognized as a sophisticated chemical factory producing compounds essential to our wellbeing—and CASDH is one of its most important molecular machines.
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