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ACE2 Protein in COVID-19: The Guardian and Gateway Zipporah Mariebelle R. Enriquez - S3999907 Xiunan(Yana) Ouyang - S3993600 Khyati Viren Shah - S4028107 Vijeta - S4032016 College of Science, Master of Biotechnology, Protein Technologies RMIT University

ABSTRACT The pandemic COVID-19 caused by SARS-CoV-2 virus, has created a demand for a comprehensive understanding of the virus's mode of human cell invasion. The human ACE2 receptor protein has been identified as central to this process. This paper delves into the structure, function, and significance of the ACE2 protein, highlighting its roles in regulation of blood pressure, immune system modulation, and cardiovascular protection. Interaction of SARS-CoV-2 with ACE2 in molecular dynamics, which facilitates viral entry and spread is also discussed. Notably, post-infection ACE2 expression patterns differ among adults, children, and genders. Given the role of ACE2 in multi-organ damage during COVID-19, potential therapeutic interventions like Orientin and Direct Blue 53 are discussed. Recognizing the ACE2 receptor's core role in COVID-19 emphasizes the importance of targeted research to combat this global health crisis. 1

Introduction The emergence of pandemic COVID-19 from the novel coronavirus SARS-CoV-2, has profoundly impacted global health, economy, and societal structures. The World Health Organization (WHO) (2020), has warned of potential spikes in extreme poverty rates due to the pandemic. This calls for urgency in global initiatives to halt virus transmission and to manage the disease. As researchers aim to understand the virus and its pathogenesis, the human ACE2 receptor protein has emerged as a significant molecule. According to Oudit et al. (2023), the ACE2 receptor has been implicated in COVID-19 as a major invasion site for SARS-CoV-2.. This receptor, which serves dual roles as an enzyme and a chaperone, is distributed across various human tissues. Given the pivotal role of ACE2 in the COVID-19 disease pathway, it becomes imperative to dissect its protein structure and function, aiming ultimately at therapeutic interventions against both SARS-CoV-2 and other potential zoonotic coronaviruses that may utilize the human ACE2 receptor. 2

The ACE2 receptor protein and its structure The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is present across different species, especially in vertebrates. The ACE2 plays a crucial role in a number of physiological processes which includes blood pressure regulation, cardiovascular functions, and fluid balance. According to Peka and Balatsky (2023), the ACE2 receptor is generally conserved across different species as can be inferred from the results of Multiple Sequence Alignments (MSAs) in Figure 1. Furthermore, interactions between humans and animals, particularly livestock, has served as opportunities for pathogens to adapt to human hosts. Figure 1 Comparison of the coding sequence of ACE2 across different species Note. Multiple Sequence Alignment results of human ACE2 with different species. The Donkey ACE2 may be considered to be the closest to the human ACE2 with an alignment score of 9756 and percent identity of 89.4 with the human ACE2. From “Analysis of RBD-ACE2 interactions in livestock species as a factor in the spread of SARS-CoV-2 among animals” by Peka, M., & 3

Viktor Balatsky, 2023, Veterinary and Animal Science , 21 , 100303–100303. https://doi.org/10.1016/j.vas.2023.100303. According to Felipe Pantoja Mesquita et al. (2023), the ACE2 receptor is implicated in the infection and spread of the severe acute respiratory syndrome (SARS) in humans and animals. This is most likely attributed to the conserved regions in the protein across species and the frequent interactions of humans with livestock animals. To gain a better understanding of the role of ACE2 in SARS in humans, its structure is analyzed. The human ACE2, has 805 amino acid sequences and is classified as a type I integral membrane. This receptor also contains a catalytic domain that functions in blood pressure homeostasis (Towler et al., 2004). Studies have also identified ACE2 as a functional receptor for coronaviruses which cause SARS. The native human ACE2 protein structure was obtained via X-ray crystallography, shown in figure 2. 4

Figure 2 Structure of the Native Human Angiotensin Converting Enzyme-Related Carboxypeptidase (ACE2) Note. The human ACE2 protein structure (Entry ID: 1R42) was retrieved from the Protein Data Bank (PDB). The protein is 76.77 kDa, obtained via X-ray crystallography with a resolution of 2.20 Å . The protein was then viewed using the Visual Molecular Dynamics (VMD) program. In the figure, alpha helices are colored purple, beta-sheets are colored yellow, beta turns are colored blue, while white and cyan are random coils in the protein. The overall structure of human ACE2 is classified under zinc metallopeptidases, where uniquely, ACE2 has two catalytic sites (Warner et al., 2004). These active sites hydrolyses or functions as a carboxypeptidase to process other proteins for various cellular processes. In a study by Geng et al. (2022b), binding between SARS-CoV-2 and human ACE2 was enhanced because of new mutations in the viral binding structural domain and conformational changes in the viral spike protein.. Much of the human ACE2 structure is conserved and can possibly be studied for inhibitors of the ACE2-coronavirus interactions. 5

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