About
James Tam holds the Lee Wee Nam Professorship and directs the Synzymes and Natural Products Center (SYNC) at Nanyang Technological University (NTU) in Singapore. His research focuses on the chemistry and biochemistry of natural product peptides, with particular emphasis on enzymatic approaches to peptide synthesis and modification.
Tam's group operates at the intersection of natural product chemistry, enzymology, and synthetic biology — developing "synzymes" (synthetic enzyme systems) that can perform the kinds of precise chemical transformations that are difficult or impossible with conventional chemistry. His group's 2014 discovery of butelase-1 from the butterfly pea plant (Clitoria ternatea) had an immediate and transformative impact on the entire field of cyclic peptide science.
Background & Career
Tam built his career at the boundary between chemistry and biology, developing expertise in peptide synthesis, natural product isolation, and enzyme biochemistry. His interest in peptide ligation enzymes arose from a longstanding question in cyclotide biology: how does the plant achieve the head-to-tail cyclisation of cyclotide precursor proteins? The answer — that a class of plant enzymes called asparaginyl endopeptidases (AEPs) are responsible — had been emerging from the work of Marilyn Anderson and others, but the practical implications for laboratory synthesis were not yet clear.
Tam's group at NTU took the question in a bold direction: instead of merely characterising the natural enzyme, they set out to isolate a specific AEP with the highest possible ligation activity, and to develop it as a practical laboratory tool. The result was butelase-1 — isolated from the butterfly pea, a common tropical plant used in Southeast Asian cuisine and traditional medicine — which proved to be not just useful but extraordinary: the fastest peptide ligase ever characterised.
Key Contributions
- Discovery of butelase-1: Isolated and characterised butelase-1 from Clitoria ternatea (butterfly pea) — the first Asn/Asp-specific peptide ligase to be described, and the fastest known peptide ligase with a kcat of up to 17 s⁻¹ and a catalytic efficiency (kcat/KM) of up to 542,000 M⁻¹ s⁻¹. Published in Nature Chemical Biology, 2014.
- 20,000× faster than sortase A: Demonstrated that butelase-1 cyclises peptides 20,000 times faster than sortase A — the enzyme that had previously been the standard enzymatic cyclisation tool in research laboratories worldwide — with yields exceeding 95% and without leaving a "scar sequence" of extra amino acids at the ligation site.
- Nature Protocols standard method: Published the butelase-mediated cyclisation protocol in Nature Protocols (2016), making the method accessible to laboratories worldwide. This protocol is now widely adopted as a standard approach for producing cyclic peptides and cyclotide variants in research settings.
- Synzyme concept: Developed the broader concept of "synzymes" — engineered enzyme systems designed specifically for natural product synthesis — extending butelase-1 work into a general platform for biosynthetic chemistry.
- Butterfly pea biochemistry: Conducted extensive characterisation of the biochemistry of Clitoria ternatea, revealing it as a rich source of bioactive peptides and enzymes with broad biotechnological potential beyond butelase-1 alone.
Why Butelase-1 Matters
Before butelase-1, producing cyclic peptides in the laboratory was technically demanding. Chemical synthesis methods require careful oxidative folding steps that are slow, low-yielding, and difficult to control. The previous enzymatic alternative — sortase A from Staphylococcus aureus — was useful but slow and left unwanted amino acid sequences at the ligation site (a "scar"), complicating downstream applications.
Butelase-1 solved both problems. It ligates peptide ends with extraordinary speed and efficiency, leaves no scar sequence, and works under mild aqueous conditions compatible with biological samples. This makes it ideal for producing cyclotide variants for structure-activity studies, for attaching functional groups to peptides, for generating cyclic libraries for drug screening, and for any application where speed, yield, and precision in peptide ligation matter.
The discovery also shed new light on plant cyclotide biosynthesis: butelase-1 is closely related to the AEP enzymes that perform cyclotide cyclisation in plants, confirming the evolutionary connection and explaining how plants achieve such efficient cyclisation in vivo.
Butelase-1 is now used in laboratories worldwide as a standard tool for producing cyclic peptides, engineering protein modifications, and generating cyclotide variants for drug design. The Nature Chemical Biology 2014 paper and the Nature Protocols 2016 method paper are among the most-cited contributions in cyclic peptide methodology of the past decade.
Key Publications
Nature Chemical Biology, 2014.
The landmark discovery paper characterising butelase-1 — its isolation from Clitoria ternatea, its remarkable kinetic parameters, its specificity, and its application to peptide cyclisation. One of the most impactful papers in cyclic peptide science of the 2010s.
Nature Protocols, 2016.
Step-by-step protocol for using butelase-1 to cyclise peptides in the laboratory — now a standard reference method used by research groups worldwide.
Multiple papers from the SYNC group at NTU describing the application of butelase-1 and related AEP ligases to the synthesis of diverse cyclic peptide natural products and analogues.
Characterisation of the butterfly pea as a natural product source — identifying the full complement of bioactive peptides and enzymes present and their potential biotechnological applications.